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

Abstract

<div>Abstract<p>Gilteritinib is a potent and selective <i>FLT3</i> kinase inhibitor with single-agent clinical efficacy in relapsed/refractory <i>FLT3</i>-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 <i>NRAS</i> or <i>KRAS.</i> Less frequently, secondary <i>FLT3</i>-F691L gatekeeper mutations or <i>BCR–ABL1</i> 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 <i>RAS</i> mutations in <i>FLT3</i>-mutated subclones, the expansion of alternative wild-type <i>FLT3</i> 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.</p>Significance:<p>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 <i>FLT3</i>-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.</p><p><i>See related commentary by Wei and Roberts, p. 998</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 983</i></p></div>