Dynamic genetic and nongenetic RAS-pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy.

RAS-pathway activation, through diverse genetic and nongenetic mechanisms, drives resistance to FLT3 and BCL2 inhibitors in AML, with resistance linked to monocytic differentiation.

• Why it matters: Understanding resistance mechanisms is crucial for improving AML therapies, as bulk sequencing cannot capture tumor heterogeneity and dynamic evolution during treatment.
• What they did: Multiomic single-cell DNA/protein and RNA/protein profiling was performed on AML patient samples from a clinical trial involving venetoclax and gilteritinib, revealing diverse resistance pathways.
• The result: Targeting RAS-pathway activation resensitized AML cells to therapy, highlighting RAS signaling as a central resistance driver and a promising therapeutic target to overcome resistance.