Dynamic genetic and nongenetic RAS pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy - PubMed
3 hours ago
- #single-cell multiomics
- #AML therapy resistance
- #RAS pathway
- Bulk sequencing alone is insufficient to identify all mechanisms of relapse due to tumor heterogeneity and on-treatment evolution.
- Single-cell multiomic profiling of AML patients treated with venetoclax and gilteritinib revealed that resistance involves RAS activation through genetic mutations, non-mutational upregulation, and a shift to monocytic differentiation.
- In vitro models showed that RAS pathway inhibition can resensitize cells to venetoclax and gilteritinib therapy.
- Convergent resistance pathways can be activated via diverse genetic and non-genetic mechanisms, with RAS signaling being central to resistance against FLT3 and BCL2 inhibitors.
- Targeting the RAS pathway is highlighted as a viable clinical strategy to overcome resistance in AML.