2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

against most imatinib-resistant BCR-ABL mutants in
vitro 4,13 and clinically. Notable exceptions are the highly
resistant T315I mutation and the moderately resistant
F317L mutation, 4 which is frequently associated with hematologic
response, rarely with cytogenetic response, and occasionally
with secondary resistance to dasatinib. 10 Other
mutations associated with clinical resistance to dasatinib
include V299L, T315A, and F317I, 4,10 which are largely
imatinib-sensitive. Nilotinib is a structural derivative of
imatinib that is similarly clinically vulnerable to a small
number of BCR-ABL kinase domain mutations, including
T315I, 14 Y253H, E255V/K, and F359C/V. 15,16 Collectively,
the three approved BCR-ABL kinase inhibitors appear to
retain activity against all BCR-ABL kinase domain mutants
associated with single nucleotide substitution, with the
exception of BCR-ABL/T315I mutants. Both dasatinib and
nilotinib have been approved for the treatment of CML in
the second line, and more recently in the first line, as a
result of improved cytogenetic and molecular response rates
associated with these agents relative to imatinib. 17,18
Commonly, the choice of a second-line BCR-ABL inhibitor
in patients is guided by the specific mutation responsible for
imatinib resistance, as well as comorbid conditions that may
influence the choice of agent. Complex substitutions, including
polyclonal (more than one mutation in a single patient)
and compound mutations (more than one mutation on a
single BCR-ABL allele), have also been reported to develop
in patients whose leukemias relapse on sequential treatment
with BCR-ABL inhibitors, 10,19 which makes the choice
of subsequent inhibitors less clear. Until recently, the T315I
mutation has remained a vexing problem. Encouragingly,
the investigational third-generation BCR-ABL inhibitor
KEY POINTS
● Clinically relevant mechanisms of resistance to targeted
therapies can provide insight into oncogenic
signaling and disease pathogenesis.
● Resistance can be divided into mechanisms that reactivate
kinase activity (“on-target”), indicating
maintained critical reliance on the target kinase, and
those that bypass kinase activity (“off-target”).
● Secondary resistance to BCR-ABL and FMS-like tyrosine
kinase 3 (FLT3) inhibitors is largely mediated
by on-target mechanisms, specifically kinase domain
mutations.
● Increased levels of primary resistance in advanced
phases of chronic myeloid leukemia and in FLT3–
internal tandem duplication mutant acute myeloid
leukemia may be indicative of cooperating lesions in
these diseases that allow bypass of oncogenic signaling
mediated by the target kinase.
● As more potent second- and third-generation BCR-
ABL and FLT3 inhibitors with broader activity
against drug resistance–causing kinase domain mutations
become available, it is anticipated that resistance
will be increasingly associated with off-target
mechanisms of resistance.
686
ponatinib has demonstrated substantial clinical activity in
patients with the T315I mutation in an interim analysis of a
pivotal phase II study, 20 with 57% of patients with CP-CML
with the T315I mutation achieving a MCyR, defined as 35%
or less Philadelphia chromosome–positive bone marrow
metaphases. Ponatinib also demonstrated clinical activity
against other drug-resistant BCR-ABL mutant isoforms in
this study. 20 Encouragingly, this agent appears to be highly
invulnerable to kinase domain mutation as a mechanism of
resistance in vitro, 21 and translational studies that define
mechanisms of resistance to this agent will be of particular
interest. It is anticipated that the ability to clinically inhibit
all BCR-ABL kinase domain mutant isoforms will likely
render off-target mechanisms of resistance increasingly relevant.
Decreased expression of the drug transporter human
organic cation transporter 1 (hOCT1), responsible for imatinib
influx, has also been correlated with suboptimal response
to imatinib, though this could be overcome with
higher doses of imatinib. 22 Pretreatment expression of
hOCT1 has also been correlated with clinical outcomes to
imatinib including response rate, progression-free survival
(PFS), and overall survival (OS). 23 It is likely, however, with
evidence of improved molecular response rates with more
potent second-generation BCR-ABL inhibitors used in the
first line 17,18 that this mechanism of clinical resistance will
become less relevant.
Off-target Resistance: BCR-ABL–Independent
Mechanisms of Resistance
SMITH AND SHAH
To date, the molecular mechanisms of clinically relevant
BCR-ABL–independent resistance remain largely uncharacterized.
It is clear that certain additional clonal cytogenetic
abnormalities are associated with progression from CP-CML
to AP-CML, decreased TKI responsiveness, and poorer prognosis.
In a large study of 1,151 patients treated with imatinib,
“major-route” cytogenetic abnormalities defined as a
second Ph chromosome, trisomy 8, isochromosome 17q, or
trisomy 19 were clearly associated with longer times to
achievement of complete cytogenetic response and major
molecular response and overall decreased PFS and OS. 24 A
recent report suggested an association between translocations
involving ecotropic viral integration site 1 (EVI1) and
TKI resistance in myeloid blast crisis disease. 25 Additionally,
the substantially lower initial hematologic response
rates to imatinib in Ph-positive ALL and AP-CML suggest
that advanced phases of disease may have decreased reliance
on BCR-ABL signaling. 2,3 The association between
acquired clonal cytogenetic abnormalities and disease progression
despite TKI therapy and the lower overall TKI
response rates observed in advanced phases of disease
suggests that select cooperating genetic alterations may
functionally bypass dependence on BCR-ABL tyrosine kinase
activity. Multiple in vitro studies have suggested that
CML cells may bypass dependence on BCR-ABL signaling
through aberrant activation of parallel or downstream signaling
pathways by other means, including overexpression
of SRC-family kinases, 26 overexpression of STAT5, 27 or
activation of the PI3K/AKT pathway. 28 However, the specific
molecular mechanisms mediating this process in patients
remain poorly defined.