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Annu. Rev. Pathol. Mech. Dis. 2008. 3:557–86

First published online as a Review in Advance on

October 16, 2007

The Annual Review of Pathology: Mechanisms of

Disease is online at pathmechdis.annualreviews.org

This article’s doi:

10.1146/annurev.pathol.3.121806.151538

Copyright c○ 2008 by Annual Reviews.

All rights reserved

1553-4006/08/0228-0557$20.00

Molecular Pathobiology

of Gastrointestinal

Stromal Sarcomas

Christopher L. Corless 1

and Michael C. Heinrich 2

Oregon Health & Science University Cancer Institute, 1 Department of Pathology,

and 2 Division of Hematology & Oncology, Oregon Health & Science University,

Portland, Oregon 97239; email: corlessc@ohsu.edu, heinrich@ohsu.edu

Key Words

gist, imatinib, tyrosine kinase inhibitor, sunitinib

Abstract

Gastrointestinal stromal tumors (GISTs) form an interesting group

of sarcomas whose unique pathobiology provides a model of how

molecularly targeted therapeutics can have a major impact on patient

welfare. Approximately 85% of GISTs are driven by oncogenic

mutations in either of two receptor tyrosine kinases: KIT or plateletderived

growth factor receptor α. We review the pivotal relationship

between specific mutations in these kinase genes, the origin and

pathologic spectrum of GISTs, and the response of these tumors

to treatment with kinase inhibitors such as imatinib and sunitinib.

Mechanisms of resistance to kinase inhibitor therapy are discussed,

and targets for the next generation of therapeutics are considered.

The rapid evolution in our understanding of GISTs, which stems directly

from the close alliance of basic and clinical researchers in the

field, illustrates the growing role of the molecular classification of

solid tumors in the development of modern oncological treatments.

557


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INTRODUCTION

During the past decade, gastrointestinal stromal

sarcomas (also known as gastrointestinal

stromal tumors or GISTs) have emerged

from historic anonymity to center stage in the

emerging field of molecularly targeted therapies

for solid tumors. The nearly simultaneous

discovery of oncogenic kinase mutations

in GISTs and introduction of kinase

inhibitor therapies have led to a rapid evolution

in our understanding of these tumors

and the biology that defines them. The pace

of these developments has been greatly accelerated

by the interplay between translational

research studies and observations made in patients,

that is, from the bench to the bedside

and back again. While parallel stories are

emerging in non–small cell carcinoma of the

lung, renal cell carcinoma, colorectal carcinoma,

and breast carcinoma, lessons learned

from the molecularly targeted treatment of

GISTs provide a remarkably informative picture

of the advantages and limitations of socalled

targeted therapeutics. Indeed, it is not

an exaggeration to state that the experience

with GISTs has helped transform solid tumor

oncology by influencing all of the following:

tumor diagnosis; the definition, prediction,

and assessment of drug response; the

definition of drug resistance; and rational approaches

to second- and third-line therapies.

Even the design of new clinical trials has been

shaped in part by what has been learned from

GISTs.

This chapter provides an overview of the

exciting developments that have resulted from

the interplay between the molecular pathology,

pharmacology, and oncology of GISTs.

An emphasis is placed on the oncogenic mutations

that lead to GIST development, the

relationship between these mutations and responses

to new classes of targeted therapeutics,

and the insights into GIST biology

that have been gained from molecular

studies.

MORPHOLOGIC AND

IMMUNOPHENOTYPIC

FEATURES OF GIST

GISTs are mesenchymal neoplasms that arise

in the muscle wall of the GI tract, usually the

stomach or small bowel, and may spread over

serosal surfaces in the abdomen and/or form

metastases in the liver. The tumors range from

less than 1 cm to more than 40 cm, with an

average of approximately 5 cm. They are generally

well circumscribed, have a fleshy pink

or tan cut surface, and may show areas of

hemorrhagic necrosis and cystic degeneration

(Figure 1).

The morphology of GISTs is quite varied.

In the 1950s they were classified as members

of the smooth muscle family of tumors, which

is understandable given the typically spindle

cell morphology of these tumors and their association

with the muscularis propria. With

the introduction of electron microscopy, and

subsequently of immunohistochemistry, the

notion that GISTs are a distinct entity began

to take hold, leading to Mazur & Clark’s proposal

in 1983 that they be called stromal tumors

(1). Ten years later the observation that

most stromal tumors arising in the GI tract are

immunopositive for CD34 led to widespread

acceptance of this new classification, although

attempts to distinguish between benign and

malignant tumors continued to generate controversy.

During the 1990s a number of investigators

noted similarities between GISTs and

a little-known population of cells in the gut

wall termed interstitial cells of Cajal (ICC),

which serve as pacemakers for peristaltic contractions.

Studies during this period showed

that Cajal cells express KIT tyrosine kinase

(CD117) and are developmentally dependent

upon stem cell factor (SCF) signaling through

this kinase (2). This led to publications by

two different groups in 1998 that GISTs commonly

express CD117 (3, 4). It is now well

established that 95% of GISTs are unequivocally

positive for CD117, and this remains the

558 Corless·Heinrich


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b

1 cm 1 cm

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c

single most specific marker available for these

tumors.

The introduction of CD117 as a marker

for GIST has helped refine the range of

morphologies observed in these neoplasms,

from rather bland spindle cell proliferations

to highly cellular epithelioid tumors with significant

nuclear pleomorphism (Figure 2).

However, reliance on CD117 in making the

diagnosis of GIST, in both routine practice

and clinical trials, has some drawbacks. First,

proper titering of the antibody is critical, as

false positive staining can lead to the misdiagnosis

of fibromatosis, leiomyosarcoma,

and other mesenchymal neoplasms as GIST

(5). As with any other immunohistochemical

marker, CD117 staining must be interpreted

in the context of other immunomarkers as well

Figure 1

Gross features of GIST. (a) Cross

section of a primary gastric GIST

(postfixation). A remnant of overlying

gastric mucosa is visible above (arrow).

(b) A large GIST metastasis resected

from the liver. (c) Metastatic GIST

nodules on the surface of the colon.

The preoperative diagnosis was stage

III ovarian carcinoma.

as of the anatomic location and morphology

of the tumor. Second, the spectrum of CD117

staining in GISTs is considerable, both in intensity

and in cellular distribution (Figure 2).

KIT is a glycoprotein receptor tyrosine kinase

that normally resides at the cell surface.

However, in some GISTs, staining for CD117

is predominantly cytoplasmic and this should

not preclude the diagnosis. Finally, recent

studies have established the existence of a subset

of GISTs negative for CD117 expression—

so-called KIT-negative GISTs. The molecular

basis for this phenomenon and its implications

for GIST biology are topics considered

later in this review.

With the above caveats in mind, CD117

contributes to the accurate diagnosis of

the great majority of GISTs. Several other

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a

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c

Figure 2

GIST morphology. (a) A spindle cell GIST intersecting with the muscularis propria ( yellow asterisks).

(b) A GIST comprising a mixture of short spindle cells and epithelioid cells. (c) Immunohistochemical

staining of KIT (CD117) in a GIST, showing a typical mixed pattern of surface membrane and

cytoplasmic positivity. (d ) Immunohistochemical staining of KIT in an epithelioid GIST, showing a

dot-like cytoplasmic pattern.

promising immunomarkers have been identified

in GISTs through molecular studies.

One is PKCθ, a member of the protein kinase

C family expressed in virtually all GISTs

and a few other cell types, principally T cells.

Immunohistochemical staining for PKCθ has

been documented in GISTs, but the commercially

available antibodies to this protein have

high backgrounds that limit their usefulness

(6–8). Staining for platelet-derived growth

factor receptor α (PDGFRA), a receptor tyrosine

kinase closely related to KIT, has been

touted as a means of identifying KIT-negative

GISTs. However, PDGFRA is expressed in

other mesenchymal tumors and the quality of

the commercially available antibodies to this

kinase casts doubt on their usefulness. More

promising is DOG-1 (discovered on GIST-1),

d

a surface membrane protein of unknown

function discovered through gene expression

analysis (9). A recently developed monoclonal

antibody to DOG-1 may prove useful

for distinguishing KIT-negative GISTs from

other sarcomas (M. van de Rijn, personal

communication).

CLINICAL FEATURES

GISTs most commonly present in the stomach

(60%) and small intestine (25%), but they

also occur in the colon, rectum, esophagus,

mesentery, and omentum (15% together) (10,

11). Case reports and small series have established

that GISTs occasionally arise in the appendix,

the gallbladder, the retroperitoneum,

and paravaginal and paraprostatic tissue

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(12–15). Primary GISTs do not develop outside

of the abdomen.

Clinical symptoms associated with GIST

include fatigue, abdominal pain, dysphagia,

satiety, and obstruction. Rarely, patients will

suffer tumor-related hypoglycemia (16). The

workup often reveals anemia related to mucosa

bleeding or intratumoral hemorrhage.

Following resection, GISTs may recur locally,

spread diffusely throughout the serosal

surfaces of the abdomen, and/or metastasize

to the liver. Advanced disease is associated

with metastases to distant sites, including

the lung and bone. Brain metastases are

rare.

EPIDEMIOLOGY OF GIST

Recent population-based studies indicate that

GISTs are more common than previously appreciated.

Reported annual incidences, expressed

as cases per million population, are

remarkably consistent: Iceland, 11; Holland,

12.7; Taiwan, 13.7; Sweden, 14.5, and Hong

Kong, 16.8–19.6 (17–21). Data from the

Surveillance Epidemiology and End Results

program in the United States show an apparently

lower incidence (6.8 per million),

but this almost certainly reflects underdiagnosis

and reporting of GIST prior to 2000

(22). Based on the figures from other countries,

there are probably between 3300 and

6000 new GIST cases per year in the United

States. The prevalence of GIST in Sweden

is estimated at 129 per million (19). In a

study of 1765 GISTs arising from the stomach,

the mean age at diagnosis was 63 years

(23). Similarly, in a series of 906 jejunal and

ileal GISTs, the mean age was 59 years (24).

Only 2.7% of gastric GISTs and 0.6% of small

bowel GISTs were detected in patients under

21 years. A slight predilection for males

has been observed in some but not all studies,

but there are no apparent differences between

races.

GISTs commonly present in older patients

in whom other malignancies may be

present. In a review of 97 GIST patients,

Agaimy & Wuensch observed a wide variety

of synchronous and metachronous malignancies,

primarily carcinomas and hematologic

cancers (25). However, no particular associations

between GIST and other malignancies

have been identified.

ONCOGENIC KIT MUTATIONS

IN GIST

KIT Mutations

In early 1998, Hirota and colleagues published

their observation of KIT kinase mutations

in GISTs, which was a groundbreaking

discovery in defining the biology of these

neoplasms (3). Studies from dozens of laboratories

worldwide have since confirmed that

60%–80% of GISTs harbor a KIT gene mutation,

that these mutations lead to constitutive

activation of the kinase, and that mutant KIT is

an excellent therapeutic target in GISTs. It is

therefore appropriate to examine the types of

KIT mutations that occur in GISTs and their

biologic implications.

KIT is a type III receptor tyrosine kinase

that is closely related to PDGFRA

and PDGFRB, as well as to macrophage

colony-stimulating factor receptor (CSF1R)

and Fl cytokine receptor (FLT3). These

kinases all share the same topology: an

extracellular ligand-binding domain comprising

five immunoglobulin-like repeats, a transmembrane

sequence, a juxtamembrane domain,

and a cytoplasmic kinase domain split

by an insert; in the case of KIT, the kinase insert

is 80 amino acids (Figure 3). Binding of

KIT ligand (SCF) to KIT results in receptor

homodimerization and kinase activation. The

resulting phosphorylation of specific tyrosines

on KIT and a number of secondary signaling

molecules promotes signaling through several

downstream pathways.

By far the most common mutations in KIT

affect the juxtamembrane domain encoded by

exon 11. Two-thirds of GISTs harbor an inframe

deletion, insertion, or substitution, or

combination thereof, in this exon (Figure 3).

www.annualreviews.org • Molecular Pathobiology of GIST 561


KIT

Extracellular domain

Exon 9 (10%)

Membrane

Juxtamembrane domain

Exon 11 (68%)

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Figure 3

Distribution of

KIT mutations in

GISTs.

Kinase I domain

Kinase II domain

(activation loop)

Approximately 10% of GISTs have a mutation

in an extracellular domain encoded by

exon 9. More rarely, mutations occur in the

kinase I (exon 13) or kinase II (exon 17) domain

(Figure 3). There is one reported tumor

with a mutation in exon 8. In general, tumors

are heterozygous for a given mutation, but

loss of the remaining wild-type KIT allele occurs

in approximately 8%–15% of tumors and

may be associated with malignant progression

(26–28).

The importance of KIT mutations in GIST

development is supported by several lines

of evidence. First, when expressed in transfected

cell lines, mutant forms of KIT show

constitutive kinase activity in the absence

of SCF, as evidenced by autophosphorylation

and activation of downstream signaling

pathways (3, 29, 30). Second, mutant KIT

is oncogenic, supporting the growth of stably

transfected BA/F3 cells in nude mice (3).

Third, phosphorylated KIT is detectable in

GIST tumor extracts. Fourth, patients with

a heritable KIT mutation are at high risk

for the development of multiple GISTs. And

finally, mice engineered to express mutant

KIT show ICC cell hyperplasia and develop

stromal tumors that resemble human GISTs

(31, 32).

Exon 13 (1%)

Exon 17 (1%)

CYTOPLASM

Signaling Pathways Activated

by Mutant KIT

Tumor extracts from KIT mutant GISTs

demonstrate strong KIT phosphorylation and

evidence of activated downstream signaling

pathways, including the MAP kinase pathway

(RAF, MEK, ERK), the STAT pathway, and

the phosphatidylinositol 3 (PI3)-kinase/AKT

pathway (Figure 4) (7, 33–35). Interestingly,

phosphorylation of STAT5, a ubiquitous finding

in hematological malignancies, is infrequently

observed in primary GISTs and GIST

cell lines, which instead show activation of

STAT3 (34, 36, 37). Surprisingly, GIST extracts

show considerable variation in the degree

of activation of the downstream pathways.

Some of these differences likely reflect

KIT mutation subtype or organ site. For example,

Duensing et al. (34) reported lower

levels of phospho-AKT and phospho-S6K but

similar levels of phospho-MAPK in KIT exon

9 mutant GISTs when compared with KIT

exon 11 mutant GISTs. Outside of the GIST

context, it is well established that different

cell types can have specific requirements for

KIT activation of downstream signaling pathways.

For example, spermatogenesis and mast

cell proliferation are both critically dependent

562 Corless·Heinrich


Stem cell

factor

KIT

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P PIP3 P PIP2 P P P

PI3K

P

P

PDK

PTEN

P

S6K

P

AKT

Figure 4

P

mTOR

Protein translation

Metabolism

Apoptosis

Gene transcription

STAT

P

P

P

SHC

P

ERK

GRB2

MEK

Cell cycle regulation

P

SOS

MAP

kinase

pathway

Major signaling pathways activated by KIT. Binding of stem cell factor leads to dimerization of KIT

proteins at the cell surface, activation of their cytoplasmic kinase domains, and phosphorylation (P) of

tyrosine residues. Phosphotyrosines provide docking sites for a complex of proteins (SHC, GRB2, SOS)

that serve to activate RAS. In turn, RAS activates the MAP kinase cascade (RAF, MEK, ERK), leading to

changes in gene expression and movement through the G1 to S phase transition of the cell cycle. STAT

phosphorylation by KIT also promotes changes in gene transcription. Finally, activation of

phosphatidylinositol 3-kinase (PI3K) by KIT leads to the conversion of phosphatidylinositol biphosphate

(PIP2) to the triphosphate (PIP3) form that allows docking of PDK and AKT at the membrane.

Phosphorylation of AKT then leads to alterations in protein translation, metabolism, and apoptosis

through the mediators S6 kinase and mammalian target of rapamycin. PTEN is a phosphatase (and

tumor suppressor) that converts PIP3 back to PIP2.

RAF

RAS

upon KIT signaling via the PI3-kinase/AKT

pathway, whereas the development of pro–

T and pro–B cell development is dependent

upon KIT-mediated activation of src kinase

family members (38–40). Further elucidation

of the critical pathways of KIT signaling involved

in GIST pathogenesis may provide

new strategies for the treatment of advanced

GIST.

Mechanisms of Mutational Activation

of KIT

Although the various mutant forms of KIT

observed in GISTs all share oncogenic properties,

there appear to be differences in their

mechanisms of activation. The juxtamembrane

domain of KIT stabilizes the kinase domain

in an inactivated, autoinhibited state by

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inserting itself into a cleft between the kinase

N and C lobes. This keeps a regulatory DFG

motif in the kinase domain in the off state,

such that access to ATP binding is impaired

by the close proximity of the so-called activation

loop (Figure 3). Mutations in exon

11 disrupt the inhibitory effect of the juxtamembrane

domain, mimicking the effects

of tyrosyl-phosphorylation of JM residues 568

and 570 (41, 42). It is unclear whether exon 11

mutant forms of KIT can heterodimerize and

signal with wild-type KIT; however, the loss

of wild-type KIT alleles in some progressing

GISTs suggests that there is selection against

the wild-type form.

In contrast to juxtamembrane mutations,

mutations in the kinase II domain encoded

by exon 17 directly affect the activation loop,

which serves as a swing arm around the DFG

hinge and helps to conformationally regulate

the ATP-binding pocket. By stabilizing the

activation loop in the extended, active conformation,

these mutations promote spontaneous

kinase activity (42, 43). Interestingly,

recent experiments by Xiang et al. (44) have

shown that the extracellular and transmembrane

domains can be eliminated from an exon

17 mutant form of KIT (D816V) and that the

kinase remains active.

Little is known of the mechanism(s) by

which the extracellular domain (exon 9) mutations

of KIT lead to increased signaling. One

possibility is that these mutations mimic the

conformational changes in the extracellular

domain induced by ligand binding (45). Alternatively,

this mutation could increase the sensitivity

of the receptor to activation by SCF.

Likewise, the mechanism by which the kinase

I domain substitution in exon 13 (K642E)

induces kinase activation has not yet been

determined.

Localization and Degradation

of Mutant KIT

Upon activation by SCF, signaling from wildtype

KIT is quickly downregulated by uptake

of the receptor from the cell surface, ubiquitinylation,

and degradation by the proteosome.

Mutant forms of KIT have significantly

longer half-lives than wild-type KIT, despite

their constitutive kinase activity. This is due

in part to their interaction with heat shock

protein 90 (HSP90), a protein chaperone that

promotes proper folding of many receptor tyrosine

kinases and other signaling molecules.

Bauer and colleagues have shown that mutant

KIT is stabilized by HSP90, and their findings

have provided the basis for a clinical trial

of an HSP90 inhibitor (46, 47).

By immunohistochemistry, KIT (CD117)

is detectable at the surface of GIST cells, as

expected. However, strong staining is commonly

observed in the cell cytoplasm and is

sometimes concentrated in a perinuclear, dotlike

pattern, suggesting that at least part of

the KIT population resides within an intracellular,

membrane-bound compartment. Although

this phenomenon has not been studied

extensively, it may reflect the accumulation

of mutant forms of KIT (48). Xiang and colleagues

have observed that KIT with an exon

17 mutation (D816V) is concentrated in the

Golgi region of transfected A375 cells (44).

Furthermore, mutant KIT modified with a

Golgi-localization motif retained its ability to

activate downstream signaling. Whether signaling

from mutant KIT can occur directly

from the Golgi in GIST cells has not been

established, but it is an interesting possibility

that may have ramifications for the activation

of downstream pathways.

ONCOGENIC PDGFRA

MUTATIONS IN GIST

Studies of GIST extracts from tumors that

lacked KIT gene mutations revealed another

receptor tyrosine kinase that was heavily phosphorylated,

which was determined to be the

α receptor for PDGFRA (49). A close homolog

of KIT, PDGFRA has similar extracellular

and cytoplasmic domains, including

a split kinase domain (Figure 5). Sequencing

of DNA from tumors with phosphorylated

PDGFRA turned up mutations in the

564 Corless·Heinrich


PDGFRA

Extracellular domain

Membrane

Juxtamembrane domain

Exon 12 (0.7%)

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Kinase I domain

Kinase II domain

(activation loop)

Exon 14 (0.1%)

Exon 18 (6.0%)

(includes D842V)

CYTOPLASM

juxtamembrane domain (exon 12) and activation

loop (exon 18). Subsequent studies identified

rare mutations in the kinase I domain

encoded by exon 14. Approximately 30% of

GISTs that are wild type for KIT, and 5%–8%

of GISTs overall, have PDGFRA gene mutations.

A number of laboratories have confirmed

that KIT and PDGFRA mutations are

mutually exclusive (48, 50, 51).

Observations supporting the significance

of PDGFRA mutations in GIST parallel those

for KIT mutations. When expressed in transfected

cell lines, mutant forms of PDGFRA

have constitutive kinase activity in the absence

of PDGF-A ligand (49, 50). As indicated

above, phosphorylated PDGFRA is

detectable in GIST tumor extracts, and the

activated downstream pathways are identical

to those in KIT mutant GISTs (49, 52). Finally,

patients with a heritable PDGFRA mutation

are at risk for developing multiple GISTs

(53, 54). Like KIT, PDGFRA is a client for

HSP90, but little work has been done in regard

to the biosynthesis and distribution of

mutant forms of PDGFRA (55).

The literature on PDGFRA mutant GISTs

emphasizes several distinctive pathologic features,

including a striking predilection for

the stomach, epithelioid morphology, myxoid

stroma, nuclear pleomorphism, and variable

(occasionally negative) expression of

CD117 (51, 56–60). The unusual epithelioid

morphology of these tumors, illustrated

in the left and middle panels of Figure 6,

raises the question of whether they are true

GISTs or whether they should be classified

as some other form of stromal tumor. There

are, however, compelling similarities between

PDGFRA mutant and KIT mutant GISTs.

Both types of tumors are immunopositive

for DOG-1 and both express PKCθ (7, 9,

56). These markers are highly selective for

GISTs over other mesenchymal tumors. In

addition, both genotypes are associated with

cytogenetic changes that are distinctive for

GIST (see GIST Progression, below) (49, 61).

Furthermore, KIT protein is detectable in

many PDGFRA mutant tumors and vice versa

(which underscores the danger of assigning a

genotype by immunohistochemistry) (9, 48,

49, 52). Note that not all PDGFRA mutant

GISTs are epithelioid; some have spindle cell

features that are indistinguishable from KIT

mutant GISTs (Figure 6, right panel).

MOLECULAR CLASSIFICATION

OF GIST

Despite their similarities, it would be improper

to regard KIT mutant and PDGFRA

Figure 5

Distribution of

PDGFRA mutations

in GISTs.

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Figure 6

Morphology of PDGFRA mutant GISTs. Three GISTs with PDGFRA mutations, illustrating the

morphologic spectrum observed in these tumors. (a) An epithelioid tumor with multinucleation.

(b) Prominent myxoid stroma in an epithelioid tumor. (c) A spindle cell tumor.

mutant GISTs as simply the same tumor

with alternate oncogenic kinases. Rather, they

are representatives of a family of closely related

tumors, which also includes the wildtype

GISTs. This puzzling subset, representing

12%–15% of all GISTs, has no detectable

KIT or PDGFRA mutations despite all efforts

to find them. What drives the growth of wildtype

GISTs remains unknown, but it is interesting

that phosphorylated KIT is detectable

in these tumors, suggesting that KIT is still

activated (7).

Classification of GISTs by kinase genotype,

as outlined in Table 1, provides a framework

for understanding their biology. For

example, the type and distribution of KIT

and PDGFRA mutations in GISTs varies with

anatomic location (Table 1). Whereas KIT

exon 9 mutations are found almost exclusively

in GISTs arising within the small intestine

and colon, the PDGFRA substitution

D842V is detectable only in GISTs arising in

the stomach, mesentery, and omentum. Other

KIT and PDGFRA mutations, by contrast, can

be found in GISTs throughout the GI tract,

from the esophagus to the rectum. These observations

correlate with recent gene expression

profiles studies of GISTs, in which both

genotype and anatomic site have a measurable

and independent impact on the patterns of

genes observed among different tumors (52,

62, 63). One possible explanation for the nonrandom

anatomic distribution of kinase mutations

is that there is more than one population

of ICC stem cells from which GISTs

may arise. Subtle differences in oncogenic signaling

from specific mutant forms of KIT

or PDGFRA may be important in sustaining

the neoplastic growth of particular ICC

populations.

Familial GIST

To date, approximately two dozen kindreds

with heritable mutations in KIT or PDGFRA

have been identified (Table 1) (7, 26, 32, 53,

64–69). Most common are single nucleotide

substitutions (or in one family, an in-frame

deletion) in KIT exon 11. The penetrance in

these kindreds appears to be high, as most

affected members will develop one or more

GISTs by middle age; however, in many patients

the tumors do not follow a malignant

course. In addition to GISTs, individuals with

exon 11 mutations may develop skin hyperpigmentation

and mast cell disease. This is

not the case for families with a KIT exon 13

or 17 mutation, suggesting that there are differences

in signaling requirements for mast

cell neoplasia as compared with GISTs. Only

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Table 1

Molecular classification of GISTs

Genetic type Relative frequency Anatomic distribution Germ line examples

KIT mutation 80%

Exon 8 Rare Small bowel 1 kindred

Exon 9 10% Small bowel, colon None

Exon 11 67% All sites Several kindreds

Exon 13 1% All sites 2 kindreds

Exon 17 1% All sites 2 kindreds

PDGFRA mutation 5%–8%

Exon 12 1% All sites 1 kindred

Exon 14


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line KIT exon 11 mutation. The remaining

five patients each had two synchronous tumors;

in four cases the tumors had matching

KIT mutations that were not germ line,

suggesting a clonal relationship. In the fifth

case the tumors had different mutations. Our

experience is similar. In addition to observing

multiple GISTs in familial GIST patients

and NF1 patients, we have analyzed

GISTs arising at different anatomic sites in

three nonsyndromic patients. In one case a

metachronous tumor had a mutation identical

to the first tumor and most likely represented

an abdominal recurrence. In the other two

cases (1 synchronous, 1 metachronous) the tumors

had differing genotypes (C.L. Corless

& M.C. Heinrich, unpublished information).

From the series by Kang et al. and our own

experience, it is apparent that patients can develop

more than one GIST without an identifiable

germ line risk factor (kinase gene or

NF1 mutation). This suggests that there are

other genes yet to be discovered that predispose

to GIST development.

KIT-Negative GISTs

In approximately 5% of GISTs, staining for

CD117 is completely negative or, at most,

equivocally positive, which leaves the morphologic

diagnosis somewhat in question. A

common misconception is that all these tumors

harbor PDGFRA mutations, but the actual

figure is more in the range of 30% (48,

50, 51). Over half of CD117-negative tumors

have KIT gene mutations, usually in exon

11, which has significant therapeutic implications

(see Treatment of GIST, below). It appears

that immunohistochemistry lacks sufficient

sensitivity to detect the small amounts

of mutant kinase that may sustain the tumor

cells in these cases. Whether a GIST can be

negative for CD117 staining and wild type for

KIT and PDGFRA is not entirely clear, as the

diagnosis must then be based strictly on exclusion.

It is likely that future studies will reveal

additional interesting variants in the stromal

tumor family.

568 Corless·Heinrich

GIST DEVELOPMENT

AND PROGNOSIS

In patients with a germ line KIT gene mutation,

multifocal proliferations of morphologically

benign, CD117-positive ICC cells are

commonly observed. These likely represent

the earliest stage of GIST development. Intriguingly,

minute growths (1 to 10 mm) of

ICC/GIST-like cells are present in 22% to

35% of thoroughly examined stomachs from

the adult population (76–78). The frequency

of KIT mutations in such incidental lesions

was reportedly low in one study, but ranged

from 46% to 85% in two other studies. A

single, subcentimeter GIST with a PDGFRA

mutation has also been reported (76). These

observations indicate that oncogenic kinase

mutations can contribute to the early development

of GISTs.

The prognostic impact of kinase mutations

has been examined in a number of retrospective

studies. Many groups have noted that KIT

exon 11 mutations are a negative prognostic

factor in clinically detected GISTs (79–

86). In particular, deletions involving codons

557 and 558 have been associated with malignant

behavior (59, 87, 88). It is possible that

mutant forms of KIT lacking these codons

generate stronger proliferative signaling than

other KIT mutations, but this remains to be

proven and the available data are insufficient

to be incorporated into routine clinical risk

assessment.

As a group, PDGFRA mutant GISTs appear

to be less aggressive than KIT mutant

GISTs (89, 90), yet PDGFRA mutant

tumors can still progress and kill patients.

Once GISTs become metastatic, kinase genotype

does not factor into overall survival (91).

Thus, although a particular kinase mutation

may set the initial course of a GIST, the prognosis

at the time of clinical presentation is

clearly influenced by other genetic events.

Unfortunately, our knowledge of these additional

mutations remains limited, and current

recommendations for assessing the risk

of progression of a newly diagnosed primary

GIST are based on three simple parameters:


Table 2

Risk stratification of primary GIST by mitotic index, size, and site

Tumor Parameters Risk of progressive disease a (%)

Mitotic index Size Gastric Duodenum Jejunum/Ileum Rectum

≤5 per 50 hpf b ≤2cm None (0%) None (0%) None (0%) None (0%)

>2 ≤ 5cm Very low (1.9%) Low (4.3%) Low (8.3%) Low (8.5%)

>5 ≤ 10 cm Low (3.6%) Moderate (24%) (Insufficient data) (Insufficient data)

>10 cm Moderate (10%) High (52%) High (34%) High (57%)

Mitotic index ≤2 cm None b High c (Insufficient data) High (54%)

>5 per 50 hpf >2 ≤ 5cm Moderate (16%) High (73%) High (50%) High (52%)

>5 ≤ 10 cm High (55%) High (85%) (Insufficient data) (Insufficient data)

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>10 cm High (86%) High (90%) High (86%) High (7%)

Table modified from Reference 137. Data based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs

(23, 24, 92).

a Defined as metastasis or tumor-related death.

b hpf, high-power field.

c Denotes small numbers of cases.

tumor size, tumor location, and mitotic index

(mitoses per 50 high-power fields). The risk

assessment scheme presented in Table 2 is

based on the work of Miettinen and colleagues

at the Armed Forces Institute of Pathology,

whose considerable efforts in studying the

outcome of patients prior to the advent of

modern therapies have provided the most

complete data available (23, 24, 92).

GIST PROGRESSION

Cytogenetic Analyses

Although oncogenic kinase mutations play a

significant role in the development of GISTs,

clearly other genetic events are important in

the clinical progression of these tumors. Cytogenetic

studies have provided clues to the

whereabouts of some of these genes. For example,

karyotypes from approximately twothirds

of GISTs demonstrate either monosomy

14, or partial loss of 14q (49, 93–97).

Interestingly, these chromosome 14 abnormalities

are observed in both KIT mutant and

PDGFRA mutant GISTs (49, 61). Based on

loss of heterozygosity and comparative genomic

hybridization studies, there are two regions

of this chromosome (14q11.2–q12 and

14q23–q24) that likely harbor tumor suppressor

genes important in early GIST formation

(94, 98).

Loss of the long arm of chromosome 22

is observed in approximately 50% of GISTs

and is associated with progression to a borderline

or malignant lesion (49, 61, 93, 94, 97,

99). Losses on chromosomes 1p, 9p, 11p, and

17p are successively less common than 14q

and 22q losses, but are more significantly associated

with malignancy (49, 61, 93, 97, 99–

102). Losses on 13q and 15q have also been

reported in GISTs (61, 99). Gains on chromosomes

8q and 17q, detected by karyotyping or

comparative genomic hybridization, are associated

with metastatic behavior (94, 103, 104).

In two recent series of GISTs analyzed

by array comparative genomic hybridization,

there was a statistically significant association

between losses on chromosome 14q and gastric

origin (61, 99). In contrast, losses on 1p

and 15q were more common among nongastric

GISTs, particularly those of the small

bowel. It will be interesting to learn which

genes at these various loci influence the development

of GISTs at different anatomic sites.

Cell Cycle Regulation

The tumor suppressor gene CDKN2A

(p16 INK4A ) on chromosome 9p is inactivated

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through several mechanisms in a significant

fraction of malignant GISTs (105–109). Deletion,

mutation, and promoter methylation all

contribute to decreased expression of p16,

which is an important inhibitor of the cell

cycle. Immunohistochemistry can be used to

assess p16 status in GISTs, and the results

correlate significantly with aggressive behavior

even in tumors classified as low risk by

standard morphological criteria (107–109).

However, the antibodies and protocols used

for p16 staining vary between laboratories,

and not all groups have confirmed the

prognostic significance of p16 (110).

Another cell cycle inhibitor, p27 KIP1 , is

also commonly downregulated in malignant

GISTs, but the association with tumor progression

is not as well supported as that for p16

(108, 110, 111). Other cell cycle regulatory

proteins that have been examined by immunohistochemistry

in GISTs include cyclins B1,

D, and E; cdc2; CDK2; CDK4; and CDK6

(108, 110, 112). Although expression of these

markers generally trends with high-risk or

malignant biology, none has been shown to

be an independent risk factor on multivariate

analysis. Amplification of the gene for cyclin

D1 (CCND1) has been associated with

GIST malignancy, but it is uncommon (8.9%)

(113). Cyclins A, Rb, and E2F1 are more

commonly detected by immunohistochemistry

in high-risk than in low-risk tumors (108,

110). Likewise, p53 expression correlates with

GIST prognosis (114, 115). However, standardized

protocols for staining and interpretation

of this marker have not been established,

and assessing loss of heterozygosity

at the p53 locus, which also correlates with

prognosis, may prove a more reliable test

(102).

TREATMENT OF GIST

The primary treatment for a resectable GIST

is surgery, which cures most patients with a

low- or intermediate-risk tumor. The lesion

should be removed intact and with clear margins,

but wide margins are not required. Lymphadenectomy

is unnecessary, save for pediatric

GISTs.

Prior to the turn of this century, the treatment

options for patients with unresectable or

metastatic GIST were poor. Chemotherapy

and radiation therapy were largely ineffective,

and the median survival for patients with advanced

disease was on the order of 18 months.

The introduction of the kinase inhibitor imatinib

(Gleevec TM ) provided the first real hope

for these patients. Survival in some cases now

exceeds six years.

Imatinib: The First Targeted

Therapeutic for GIST

Imatinib is an orally bioavailable 2-phenylpyrimidine

derivative developed in the 1990s

as a treatment for chronic myelogenous

leukemia. Imatinib shuts off oncogenic signaling

from the fusion oncogene BCR-ABL

in chronic myelogenous leukemia cells by occupying

the ATP-binding pocket of the ABL

kinase domain. ABL shares considerable homology

with the type III receptor tyrosine

kinase family, a fortuity that led to two important

observations: first, that imatinib can

inhibit in vitro a mutant form of KIT commonly

found in GISTs; and second, that imatinib

can inhibit the growth of cultured GIST

cells that have a KIT mutation (29, 30). In turn,

these experiments led to a compassionate-use

trial of imatinib in a patient with advanced

GIST and the patient reached a partial remission

in a matter of weeks (116). Subsequent

phase I/II and phase III trials conducted

worldwide have established imatinib as the

primary medical therapy for GIST.

Imatinib reliably achieves disease control

in 70%–85% of patients with advanced

KIT-positive GISTs, and the median

progression-free survival is 20 to 24 months.

The estimated median overall survival time

following initiation of imatinib therapy exceeds

36 months in all larger clinical studies

performed to date. These results are superior

to historical data on either surgery

or chemotherapy for treatment of advanced

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GISTs. For example, in a large series of

patients with advanced GISTs treated with

front-line doxorubicin-based chemotherapy,

the median survival was only nine months. On

the basis of the results of a U.S.-Finnish phase

II GIST study and the clinical studies of imatinib

for treatment of chronic myelogenous

leukemia, imatinib was approved by the Food

and Drug Administration for the treatment of

unresectable and metastatic GISTs in 2002.

Two randomized, multicenter phase III trials

to compare the relative efficacy of 400 mg

versus 800 mg of imatinib per day were

conducted in Europe/AustralAsia and North

America. The trial designs were similar except

for different primary end points (progressionfree

survival in the European/AustralAsian

trial versus overall survival in the North

American study). In both studies the objective

response rates were equivalent for

400 mg and 800 mg imatinib. However, the

800-mg dose produced a significantly longer

progression-free survival in the European/

AustralAsian trial and a trend toward improved

progression-free survival in the

higher-dose arm in the North American study.

However, more dose reductions (16% versus

60%) were seen in the higher-dose arm in the

European/AustralAsian trial. As noted below,

the apparent advantage of the 800-mg dose in

Table 3

terms of progression-free survival was greatest

in patients whose tumor had a KIT exon

9 mutation. To date, there is no significant

difference in overall survival between the two

treatment arms in either trial.

Kinase Mutations Predict Response

to Imatinib Therapy

A notable feature of the clinical studies of imatinib

for treatment of GIST is the consistent

observation that genotypically defined subsets

of GIST have different outcomes during imatinib

treatment. Table 3 lists the correlations

between tumor genotype and objective response

(both complete and partial responses)

in four trials (phases I–III). On the basis of

768 genotyped GISTs, the objective response

rates for KIT exon 11 mutant, KIT exon 9 mutant,

and wild-type GISTs are 72%, 38%, and

28%, respectively. Likewise, the probabilities

of primary resistance to imatinib for KIT exon

11, KIT exon 9, and wild-type GISTs are 5%,

16%, and 23%, respectively. An even more

striking observation is that kinase genotype

correlates with progression-free and overall

survival, with superior survival seen for patients

whose GIST harbors a KIT exon 11

mutation. For example, the median time to tumor

progression for patients whose GIST has

Relationship between kinase genotype, response, and outcome on imatinib therapy

European phase

I/II (n = 37)

B2222 phase II

(n = 127)

European/

AustralAsian

phase III

(n = 363)

North American

SWOG S0033

phase III

(n = 324)

Weighted

average

Objective response a % (n) % (n) % (n) % (n) % (n)

KIT exon 11 83% (24) 83% b (85) 70% b (248) 67% b (211) 71% (568)

KIT exon 9 25% (4) 48% (23) 35% (58) 40% (25) 38% (110)

No mutation 33% (6) 0% (9) 25% (52) 39% (33) 28% (100)

Progressive disease

KIT exon 11 4% 5% 3% 8% 5%

KIT exon 9 0% 17% 17% 16% 16%

No mutation 33% 56% 19% 21% 23%

Reference(s) (138) (27) (117) (139)

a Defined as complete or partial response by SWOG (B2222) or RECIST criteria (all other trials); excludes nonevaluable patients.

b Statistically significant difference versus KIT exon 9 and no mutation groups.

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an associated KIT exon 11 mutation is more

than one year longer than for patients whose

tumors have KIT exon 9 or wild-type kinase

genotypes. A similar overall survival benefit is

seen for patients with KIT exon 11 mutations

versus the other common genotypic subsets.

The above results reflect pooled data from

clinical studies in which imatinib doses ranged

from 400–800 mg per day. In a recent subset

analysis of the European/AustralAsian phase

III trial, Debiec-Rychter and colleagues found

that the progression-free survival of GIST patients

with KIT exon 9 mutations was significantly

better when they were treated with

800 mg per day as compared with 400 mg

per day (117). In contrast, patients whose

GIST had KIT exon 11 mutations had a similar

progression-free survival on either dose.

Many GIST experts now recommend routine

tumor genotyping and dose selection on the

basis of the presence or absence of a KIT exon

9 mutation. Similar correlative analyses are

under way using genotyping data and outcomes

from the North American phase III

study, and a meta-analysis of both trials will

be completed in late 2007.

Treatment of PDGFRA Mutant

GIST with Imatinib

Only small numbers of patients with PDGFRA

mutant GIST were included in the original

phase I–III trials, in part because an entry criterion

was positive staining for CD117. On

the basis of in vitro data, the most common

PDGFRA mutation in GISTs, D842V, is fully

resistant to the effects of imatinib (27, 50, 118,

119). The homologous KIT mutation, D816V,

is also resistant, but this mutation occurs in

mastocytosis and is not a primary mutation

in GIST. Among six patients whose GIST

harbored a PDGFRA D842V mutation, there

were no objective responses; stable disease was

observed for a few months in some of the patients.

Note, however, that up to one-third of

PDGFRA mutations are imatinib sensitive in

vitro, and individual patients with these types

of GIST have shown excellent responses to

imatinib. Thus, genotyping has an important

role in predicting the imatinib responsiveness

of PDGFRA mutant GISTs.

Effects of Imatinib on GISTs

In a phase I/II trial for the treatment of

advanced GIST with imatinib, consented

patients underwent pretreatment and posttreatment

biopsies so that fresh tumor material

could be examined and compared for

evidence of drug effects. Immunoblotting experiments

demonstrated a marked decrease in

KIT phosphorylation in extracts from tumors

biopsied five to seven days after the start of

treatment (120). These data provide direct evidence

that imatinib inhibits KIT kinase activity

in GIST cells in vivo. The correlation between

clinical response and the inhibition of

KIT signaling supports the concept that most

GISTs are dependent upon, or addicted to,

oncogenic kinase signaling. Consistent with

this view, extracts of tumors that did not respond

to imatinib continued to show KIT

phosphorylation.

One issue that has arisen in clinical

trials of imatinib is how best to assess

tumor response. By standard (RECIST) criteria,

which were originally developed for evaluating

responses to chemotoxic agents, partial

response is defined as at least a 30% decrease

in the greatest tumor diameter on a CT scan.

However, imatinib trials have established that

patients whose tumors remain stable in size

(no growth) during the first six months of

treatment enjoy the same clinical benefit as

those who have a partial response by RECIST;

that is, the time to treatment failure and the

overall survival of patients with stable disease

are the same as for those with radiographic

responses. One explanation for this is that

the effect of imatinib is more cytostatic than

cytotoxic. This view is supported by FDG-

PET scanning, which assesses glucose uptake

in solid tumors. In GISTs that respond

well to imatinib, PET scans performed within

24 hours of the first dose of imatinib show a

significant decrease in FDG signal (121). This

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in vivo evidence suggests that one of the initial

effects of kinase inhibition in GISTs is a decrease

in glycolytic metabolism. As a result of

the experience with imatinib, new criteria for

evaluating tumor response have been developed

for both PET and CT scans (121, 122).

Beyond changes in metabolism, what happens

to GIST cells when kinase signaling is

suppressed by imatinib? This has not been

studied systematically, but from published observations

and cases examined in our laboratories

there are at least three potential outcomes

in the face of imatinib treatment: (a) The tumor

cells may undergo apoptosis; (b) the tumor

cells may exit the cell cycle and show evidence

of myogenous differentiation; or (c) the

tumor cells may escape inhibition and become

drug resistant. Figure 7 illustrates a KIT exon

11 mutant GIST that showed a dramatic decrease

in cellularity within one week of starting

therapy, leaving behind a characteristically

myxoid stroma. The striking tumor cell

dropout in this case almost certainly reflects

massive apoptosis, similar to the apoptosis observed

in cultured GIST cells within 72 hours

a

of imatinib exposure (30). This reduction in

tumor cells accounts for the decreased attenuation

commonly observed by CT in responding

GIST lesions. Although the mechanisms

involved in GIST apoptosis have not been

detailed, suppression of the PI3-kinase/AKT

pathway represents one possibility. Sharma

et al. recently compared several cell lines dependent

upon various oncogenic kinases and

observed that a common event in response

to targeted kinase inhibition was an increase

in phospho-p38 MAPK, an AKT-regulated

effector of apoptosis (123). Another apoptosis

effector directly implicated in GIST cells

is the soluble form of histone H2AX, levels

of which are suppressed by oncogenic KIT

signaling by way of PI3-kinase (124). Treatment

of GIST cells with imatinib results in

the accumulation of H2AX, which in turn

causes chromatin aggregation and blocks normal

transcription.

Agaram and colleagues recently examined

a series of 43 GIST lesions resected from

28 patients who were clinically responsive

to imatinib (125). Histologic responses in

Pretreatment Day 7

b

Figure 7

Morphologic

changes post

imatinib therapy.

Comparison of

biopsies taken

pretreatment and on

day 7 of treatment

with imatinib,

showing a dramatic

decrease in tumor

cellularity. The

emergence of a

myxoid stroma in

treated lesions is

quite typical. Most of

the remaining cells

were KIT (CD117)

immunopositive.

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these tumors after 1 to 31 months of treatment

ranged from 90% reduction

in tumor cellularity. Surprisingly, few lesions

showed a complete loss of tumor cells, and responses

overall did not correlate with primary

kinase genotype or with the duration of treatment.

However, the residual tumor cells in

75% of the lesions were quiescent, as judged

by an absence of mitoses and a proliferative

index of 0% by Ki-67 staining. These cells

continued to express CD117, but in addition

some showed transdifferentiation toward a

smooth muscle phenotype, which was evident

by immunohistochemistry (desmin, smooth

muscle actin), by electron microscopy, and

by gene expression analyses using microarrays

and real-time PCR. Thus, under imatinib suppression,

GIST cells may avoid apoptosis by

exiting the cell cycle and expressing genes associated

with a differentiated phenotype. This

is analogous to the maturation commonly observed

in germ cell tumors after cisplatinbased

chemotherapy, wherein only mature

teratoma is detected in residual tumor masses.

Changes in tumor cellularity and differentiation

in the wake of imatinib treatment

are often accompanied by changes in the tumor

stroma. A paucicellular, myxoid matrix

is commonly observed (Figure 7, right), but

varying degrees of hemorrhage, cystic degeneration,

or fibrosis may also be present. In

some cases, areas of cartilaginous or osseous

differentiation may be evident, although it remains

unclear whether it is the background fibroblast

cells or residual tumor cells that are

responsible (126).

Imatinib Resistance

Responses to imatinib treatment in the setting

of unresectable or metastatic GIST vary

among patients. In many cases, there is a rapid

decrease in the attenuation of tumors on a CT

scan or a decrease in FDG uptake on a PET

scan, indicative of an excellent response. In

other cases, the tumors show relatively little

radiographic change, but their growth is arrested

for many months. A minority of patients

experience continued tumor growth on

imatinib within the first six months of treatment,

which is referred to as primary resistance.

Compared with patients who have KIT

exon 11 mutant tumors, those with exon 9 mutant

or wild-type tumors are overrepresented

in this group (Table 3). Among patients who

benefit from treatment beyond six months, a

significant fraction will show growth in one

or more lesions between 12 and 36 months

of treatment. This is termed secondary

resistance.

The molecular basis of resistance has been

the subject of active investigation. In a recent

follow-up to a phase I/II study of imatinib for

advanced GIST, biopsies from progressing lesions

were compared between 10 patients with

primary resistance (median time to treatment

failure 3.6 months) and 33 with secondary

resistance (median time to treatment failure

20.2 months) (120). In the latter group, 67%

had one or more new, acquired mutations in

KIT. Figure 8 illustrates the distribution of

the mutations, which were single nucleotide

substitutions affecting codons in the ATPbinding

pocket or the activation loop. When

engineered into a KIT cDNA with a primary

exon 11 mutation, these acquired mutations

conferred moderate- to high-level resistance

to imatinib in vitro. Moreover, two GIST cell

lines selected for imatinib resistance were also

found to contain acquired mutations (V654A

and D820A). Knockdown of KIT by the addition

of shRNA to one of these cell lines

effectively turned off signaling through the

AKT pathway, indicating that the cells were

still dependent upon mutant KIT signaling

(120).

Acquired mutations in the setting of secondary

imatinib resistance have been documented

by a growing number of laboratories

(Figure 8), establishing this as the most common

mechanism for drug escape (120, 127–

133). The resistance may manifest in a number

of ways, including growth of a nodule

within a preexisting, clinically quiescent lesion,

the development of one or more new

nodules, or widespread expansion of lesions

574 Corless·Heinrich


7

6

5

3

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1

E13 654 E13 670 E15/16 709 716 E17

Figure 8

V

ATP binding

7

5

T

S

D

5

1

6

4

4

809 816 820 822 823

C D D N Y

Distribution of acquired KIT mutations associated with imatinib resistance in GIST. Histogram showing

the relative frequency of acquired KIT mutations at the indicated codons present in exons (E) 13 through

17. Figure adapted with permission from Reference 120.

throughout the liver or abdominal cavity. An

interesting phenomenon now documented in

several studies is the presence of different

resistance mutations within different tumor

nodules, and even within different regions

of a single nodule (120, 127, 134, 135). Recent

experiments in our laboratories using

high-sensitivity real-time PCR indicate that

imatinib-resistant GISTs are often heterogeneous,

with up to three other acquired mutations

detectable at low levels in the background

of a dominant resistance mutation

(C.L. Corless & M.C. Heinrich, unpublished

results). Whether these resistance mutations

exist before imatinib treatment or arise de

novo during therapy has yet to be determined.

Regardless, the heterogeneity of resistance

has important implications in regard to salvage

therapies.

Aside from acquired mutations, there are

other potential causes for secondary resistance.

Occasional tumors show evidence of

KIT gene amplification (127, 129). More

rarely, there is downregulation of KIT

expression, suggesting the emergence of a

KIT-independent phenotype. In their series

of resected GISTs from imatinib-treated patients,

Agaram and colleagues identified several

mitotically active lesions that were p53

immunopositive and two tumors that had p53

2

Activation loop

4

3

2

2

4

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Table 4

mutations (125). It is likely that dysregulation

of the cell cycle through such mutations contributes

to imatinib resistance.

In contrast to tumors in the setting of secondary

imatinib resistance, those in patients

with primary resistance do not show acquired

mutations (120). In some of these cases, treatment

failure is related to underdosing of imatinib,

as clinical improvement can be observed

when the dose is increased to 800 mg per day.

This is particularly true for tumors with a KIT

exon 9 mutation. In the majority of primary

resistance cases, however, the mechanism for

drug escape remains unknown.

NEW KINASE INHIBITORS AND

OTHER TREATMENT TARGETS

Success with imatinib has spurred the development

of many new kinase inhibitors with

activity against KIT and PDGFRA (Table 4).

Among these is sunitinib (Sutent TM ), an orally

bioavailable butanedioic acid derivative considered

a multitargeted inhibitor because it

also blocks VEGFR2 and thereby impairs tumor

angiogenesis. Sunitinib is FDA-approved

for the treatment of GIST patients who are

intolerant of, or resistant to, imatinib. On

the basis of an extended phase II trial, it ap-

Targeted therapeutics for the treatment of GIST

Drug type Drug Status

Kinase inhibitors Imatinib (Gleevec) FDA approved

Sunitinib (Sutent) FDA approved

Nilotinib (Tasigna) FDA approval pending

Dasatinib (Sprycel) FDA approval pending

PTK787

In trials

AZD2171

In trials

OSI-930

In trials

XL-820

In trials

AB-1010

In trials

HSP90 inhibitors IPI-504 In trials

CNF-2024

In trials

KOS-1022

In trials

mTOR inhibitor RAD001 In trials

BCL-2 inhibitor Genasense In trials

HDAC inhibitors FR901228 In trials

LBH 589

In trials

pears that the best responses to this drug are

in patients with KIT exon 9 mutant or wildtype

tumors (136). There is comparatively little

benefit to patients whose tumors have acquired

imatinib-resistance mutations, as many

of these mutations (particularly those in exon

17) confer cross-resistance to sunitinib. Predictably,

patients who initially respond well

to sunitinib may develop secondary resistance,

and preliminary studies in our laboratories indicate

that sunitinib-specific resistance mutations

occur in this setting (136a).

One conclusion, then, from the experience

with imatinib and sunitinib is that monotherapy

with a kinase inhibitor will often lead to

treatment failure owing to the acquisition of

resistance mutations. To what extent all the

other inhibitors now in preclinical and clinical

development will prove useful in the management

of GISTs remains to be determined, but

the need for multi-agent treatment modalities

is already quite clear. These could take the

form of a kinase inhibitor cocktail or could

be a combination of a kinase inhibitor with

another targeted therapeutic.

One target already examined in the setting

of imatinib resistance is mammalian target of

rapamycin, which is suppressed by the drug

RAD001. Some responses have been observed

with this therapy, but its potential for imatinib

salvage appears limited. Perhaps more

promising is the HSP90 inhibitor, IPI-504.

A derivative of 17-AAG (geldanamycin), this

compound is more potent in vitro against

imatinib-resistant forms of KIT than against

wild-type or exon 11 mutant KIT, presumably

because additional mutations destabilize

the protein and make it more dependent on

HSP90 chaperone activity (46). Many other

potential targets, such as MEK, PI3-kinase,

and AKT, remain to be explored. There is also

the possibility of adding an anti-angiogenic

agent (e.g., bevacizumab) to a kinase inhibitor

to slow tumor progression, or combining an

inhibitor with a traditional chemotoxic agent

with the goal of increasing initial tumor apoptosis

and limiting the pool of cells that can

become resistant.

576 Corless·Heinrich


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CONCLUSIONS

Progress in our understanding of GIST biology

laid the groundwork for the first breakthroughs

in GIST treatment. In turn, the outcomes

of GIST patients being treated with

kinase inhibitors are informing ongoing studies

of drug resistance, downstream signaling,

apoptosis, and synergistic strategies for tumor

suppression. This interplay between basic tumor

biology and the effects of targeted therapeutics

in patients provides a model for accelerating

the development of novel, rationally

based treatment strategies. This model is now

being widely adopted in programs focusing on

a variety of other solid tumors.

DISCLOSURE STATEMENT

Kinase genotype has emerged as a principal

factor in the evaluation of GISTs, particularly

those tumors that are overtly malignant

or have a high risk of recurrence. In

addition to helping establish the diagnosis of

GIST in unusual cases, genotyping can be

very useful to physicians and patients in deciding

on imatinib dose, in estimating the likelihood

and duration of benefit, and potentially

in selecting second-line therapies. For

all these reasons, the 2007 National Comprehensive

Cancer Network guidelines for

GIST support routine kinase genotyping for

all newly diagnosed high-risk and malignant

tumors.

Drs. Corless and Heinrich have both received consulting fees and honoraria from Novartis

and Pfizer during the past two years. Dr. Heinrich has an equity interest in MolecularMD.

ACKNOWLEDGMENTS

The authors wish to acknowledge all the members of their laboratories for their tireless devotion

to GIST research. Some of the work referenced in this chapter was supported by

donations from the GIST Cancer Research Fund and by grant support from the LifeRaft

Group.

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Contents

Annual Review

of Pathology:

Mechanisms

of Disease

Volume 3, 2008

Annu. Rev. Pathol. Mech. Dis. 2008.3:557-586. Downloaded from arjournals.annualreviews.org

by Oregon Health & Science University on 02/02/08. For personal use only.

The Relevance of Research on Red Cell Membranes to the

Understanding of Complex Human Disease: A Personal Perspective

Vincent T. Marchesi ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣1

Molecular Mechanisms of Prion Pathogenesis

Adriano Aguzzi, Christina Sigurdson, and Mathias Heikenwalder ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣11

The Aging Brain

Bruce A. Yankner, Tao Lu, and Patrick Loerch ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣41

Gene Expression Profiling of Breast Cancer

Maggie C.U. Cheang, Matt van de Rijn, and Torsten O. Nielsen ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣67

The Inflammatory Response to Cell Death

Kenneth L. Rock and Hajime Kono ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣99

Molecular Biology and Pathogenesis of Viral Myocarditis

Mitra Esfandiarei and Bruce M. McManus ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣127

Pancreatic Cancer

Anirban Maitra and Ralph H. Hruban ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣157

Kidney Transplantation: Mechanisms of Rejection and Acceptance

Lynn D. Cornell, R. Neal Smith, and Robert B. Colvin ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣189

Metastatic Cancer Cell

Marina Bacac and Ivan Stamenkovic ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣221

Pathogenesis of Thrombotic Microangiopathies

X. Long Zheng and J. Evan Sadler ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣249

Anti-Inflammatory and Proresolving Lipid Mediators

Charles N. Serhan, Stephanie Yacoubian, and Rong Yang ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣279

Modeling Morphogenesis and Oncogenesis in Three-Dimensional

Breast Epithelial Cultures

Christy Hebner, Valerie M. Weaver, and Jayanta Debnath ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣313

v


The Origins of Medulloblastoma Subtypes

Richard J. Gilbertson and David W. Ellison ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣341

Molecular Biology and Pathology of Lymphangiogenesis

Terhi Karpanen and Kari Alitalo ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣367

Endoplasmic Reticulum Stress in Disease Pathogenesis

Jonathan H. Lin, Peter Walter, and T.S. Benedict Yen ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣399

Autophagy: Basic Principles and Relevance to Disease

Mondira Kundu and Craig B. Thompson ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣427

Annu. Rev. Pathol. Mech. Dis. 2008.3:557-586. Downloaded from arjournals.annualreviews.org

by Oregon Health & Science University on 02/02/08. For personal use only.

The Osteoclast: Friend or Foe?

Deborah V. Novack and Steven L. Teitelbaum ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣457

Applications of Proteomics to Lab Diagnosis

Raghothama Chaerkady and Akhilesh Pandey ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣485

The Pathology of Influenza Virus Infections

Jeffrey K. Taubenberger and David M. Morens ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣499

Airway Smooth Muscle in Asthma

Marc B. Hershenson, Melanie Brown, Blanca Camoretti-Mercado,

and Julian Solway ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣523

Molecular Pathobiology of Gastrointestinal Stromal Sarcomas

Christopher L. Corless and Michael C. Heinrich ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣557

Notch Signaling in Leukemia

Jon C. Aster, Warren S. Pear, and Stephen C. Blacklow ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣587

The Role of Hypoxia in Vascular Injury and Repair

Tony E. Walshe and Patricia A. D’Amore ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣615

Indexes

Cumulative Index of Contributing Authors, Volumes 1–3 ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣645

Cumulative Index of Chapter Titles, Volumes 1–3 ♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣♣647

Errata

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease

articles may be found at http://pathol.annualreviews.org

vi

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