2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Mechanisms of Resistance to Targeted
Therapies in Acute Myeloid Leukemia and
Chronic Myeloid Leukemia
By Catherine C. Smith, MD, and Neil P. Shah, MD, PhD
Overview: Small molecule kinase inhibitors of BCR-ABL in
chronic myeloid leukemia (CML) and of FMS-like tyrosine
kinase 3 internal tandem duplication (FLT3-ITD) in acute
myeloid leukemia (AML) have been successful at achieving
remissions in these diseases as monotherapy, but these
leukemias do not initially respond in a subset of patients
(primary resistance) and they progress in an additional group
CLINICALLY EFFECTIVE small molecule inhibitors
that target pathologically activated tyrosine kinases
have become increasingly prevalent as cancer therapeutics.
Identification of resistance mechanisms in patients treated
with clinically active targeted therapeutics can yield critical
insights into the importance of specific pathways in human
cancers. Though the first highly successful molecularly “targeted”
therapeutic in leukemia was all-trans retinoic acid,
which promotes the differentiation of acute promyelocytic
leukemic blasts driven by the fusion protein PML-
RARalpha, mechanisms of resistance responsible for clinical
resistance to this agent remain poorly defined. Therefore,
this review will focus on emerging data surrounding clinical
resistance mechanisms to tyrosine kinase inhibitors (TKIs)
in CML and AML, which target oncogenic tyrosine kinases.
CML: A Model of Resistance to Targeted Therapy
The remarkable success of the small molecule inhibitor
imatinib, which achieves remissions in CML in all phases of
disease, ushered in a new era of molecularly targeted therapeutics
and created a new paradigm for the treatment of
cancer. Though CML in a small percentage of patients with
chronic phase CML (CP-CML) does not respond to imatinib
initially (primary resistance), the overall hematologic and
major cytogenetic response (MCyR) rates (95.3% and 85.2%,
respectively) are exceedingly high in newly diagnosed patients.
1 Response rates in the advanced phases of CML
(accelerated and blast phases; AP-CML) are substantially
lower, and remissions in AP-CML are typically shortlived.
2,3 Additionally, a proportion of patients with CP-CML
also experiences relapse despite continuation of treatment
(secondary resistance). Elucidation of the molecular mechanisms
responsible for clinical resistance to effective targeted
therapeutics can lead to strategies to improve clinical outcomes
and also provide important insights into the role of
specific molecular targets in disease pathogenesis. To this
end, studies that interrogate primary patient samples are
most likely to both affect clinical management and be most
relevant to disease. Illustrative of this point, paradigmatic
studies of mechanisms of relapse on imatinib in patients
with CML confirmed the importance of BCR-ABL as critical
for CML pathogenesis; facilitated the development of the
effective second-generation inhibitors dasatinib and nilotinib,
which are effective against most imatinib-resistant
mutations 4,5 ; and informed studies of secondary resistance
mechanisms to active targeted therapies in a variety of
malignancies. Resistance to targeted therapies can be conceptualized
in two major categories, which can inform efforts
of patients after an initial response (secondary resistance).
Resistance to these agents can be divided into mechanisms
that allow reactivation kinase activity and those that bypass
reliance on oncogenic signaling mediated by the target kinase.
Elucidation of clinical resistance mechanisms to targeted
therapies for patients can provide important insights into
disease pathogenesis and signaling.
to override resistance: (1) “on-target” resistance, whereby
the disease remains dependent on aberrant signaling mediated
by the target oncogene, and (2) “off-target” resistance,
whereby activation of downstream or parallel signaling
pathways bypasses tumor dependence on the target oncogene
(Fig. 1).
On-target Resistance: BCR-ABL–Dependent
Mechanisms of Resistance
In a seminal report, Gorre and colleagues evaluated 11
patients with advanced phase Philadelphia (Ph) chromosome–positive
CML or acute lymphoblastic leukemia (ALL)
whose leukemias relapsed after initially responding to imatinib
and found reactivation of BCR-ABL kinase activity at
the time of relapse in all cases, most commonly by gene
amplification (three patients) or point mutation in the BCR-
ABL kinase domain (six patients), specifically a C3T substitution
coding for an isoleucine substitution at Thr 315 (the
“gatekeeper” residue) predicted to impair imatinib binding 6
by blocking access to a deeper hydrophobic pocket at the
ATP binding site in the kinase domain of BCR-ABL. This
mutation has been subsequently shown to mediate resistance
to dasatinib and nilotinib as well. 5,7 The findings of
Gorre and colleagues confirmed the continued central dependence
of CML on BCR-ABL kinase activity. A second mechanism
of clinical resistance provided by Gorre and
colleagues was genomic amplification of the BCR-ABL
genomic locus, with presumed overexpression of BCR-ABL
mRNA and protein. Though others have reported clinical
resistance to be associated with BCR-ABL overexpression or
the acquisition of additional Ph chromosomes, 8 numerous
studies have confirmed that BCR-ABL kinase domain mutations
represent the most common cause of relapse in all
phases of disease, 9-11 both for imatinib and the secondgeneration
BCR-ABL inhibitors dasatinib and nilotinib.
Although clinical resistance to imatinib has been associated
with more than 90 different resistance-causing kinase
domain mutations to date, 12 the second-generation inhibitors
dasatinib and nilotinib are vulnerable to far fewer
resistance-conferring mutations. Dasatinib has activity
From the Division of Hematology/Oncology, University of California, San Francisco, CA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Neil P. Shah, MD, PhD, Division of Hematology/Oncology,
UCSF, 505 Parnassus Avenue, Suite M1286, Box 1270, San Francisco, CA 94143; email:
nshah@medicine.ucsf.edu.
© 2012 by American Society of Clinical Oncology.
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