2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Conclusion
The overall success of small molecule inhibitors targeted
against BCR-ABL in CML has spurred the development of
inhibitors targeting other pathologically activated kinases.
The on-target BCR-ABL TKI resistance mechanism paradigm
has been implicated as operative in a number of other
malignancies associated with clinically active kinase
inhibitors, 41-43 now including FLT3-ITD–positive AML. In
particular, the concept that many relapses occur because of
Authors’ Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Catherine C. Smith Astellas
Neil P. Shah ARIAD; Bristol-
Myers Squibb;
Novartis
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mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib
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688
the reactivation of oncogenic kinase activity mediated by
on-target mutation, amplification, decreased drug influx, or
increased ligand activation seems to be particularly clinically
relevant and has led to rekindled interest in developing
potent selective FLT3 inhibitors. As inhibitors with increased
potency/selectivity and decreased vulnerability to
resistance-conferring mutations become available, it is anticipated
that off-target mechanisms of resistance, such as
activation of parallel or downstream signaling pathways,
will be more prominent in both CML and AML.
Stock
Ownership Honoraria
REFERENCES
Research
Funding
Ambit; ARIAD;
Bristol-Myers
Squibb;
Plexxikon
Expert
Testimony
SMITH AND SHAH
Other
Remuneration
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