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Ref Type Journal Article
PMID (31088841)
Authors McMahon CM, Ferng T, Canaani J, Wang ES, Morrissette JJD, Eastburn DJ, Pellegrino M, Durruthy-Durruthy R, Watt CD, Asthana S, Lasater EA, DeFilippis R, Peretz CAC, McGary LHF, Deihimi S, Logan AC, Luger SM, Shah NP, Carroll M, Smith CC, Perl AE
Title Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 9 8 2019 Aug 1050-1063 Cancer Discov
URL
Abstract Text Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983.

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