Kinome profiling of venetoclax-resistant wild type and NRAS-G12C MOLM-14 cells

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. Kinome profiling of Molm14 cells, both NRAS WT and NRAS G12C, both treatment-naive and venetoclax resistant, additionally shows RAS upregulation with venetoclax resistance. 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Christine Berryhill  

LAB HEAD: Catherine Smith

PROVIDER: PXD068585 | Pride | 2026-06-15

REPOSITORIES: Pride