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RAS pathway activation drives clonal selection and monocytic differentiation in FLT3 and BCL2 inhibitor resistance

ABSTRACT: Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324062 | GEO | 2026/04/01

REPOSITORIES: GEO

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