Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia.

ABSTRACT: 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 targe

SUBMITTER: McMahon CM 

PROVIDER: S-EPMC11994087 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature