Dynamic genetic and nongenetic RAS-pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy.
Vanessa E Kennedy, Cheryl A C Peretz, Anushka Walia et al.
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In 30 seconds
This phase 1b clinical trial investigated the mechanisms of resistance to the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib in patients with acute myeloid leukemia (AML). The study found that resistance was linked to RAS pathway activation through various genetic and nongenetic mechanisms, including the emergence of RAS-mutant clones and transcriptional upregulation. RAS-pathway inhibition was shown to resensitize resistant cells to treatment.
Key findings
- Resistance to Ven/Gilt was associated with RAS activation through multiple mechanisms.
- FLT3-mutant clones were effectively eliminated, but RAS-mutant clones emerged.
- Nonmutational upregulation of RAS transcriptional programs contributed to resistance.
- Inhibition of RAS signaling resensitized cells to Ven/Gilt in vitro.
Why it matters
Understanding the mechanisms of resistance in AML can inform treatment strategies. The findings suggest that targeting the RAS pathway may enhance the effectiveness of existing therapies, potentially improving patient outcomes.