A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.

ABSTRACT: Mutations activating RAS/RAF/MEK/ERK signaling are associated with poor outcome in acute myeloid leukemia (AML), but therapeutic targeting of this pathway is challenging. Here, we employ a structure-based, dynamic RAS pathway model to successfully predict RAF inhibitor (RAFi) combinations which synergistically suppress ERK signaling in RAS-mutant AML. Our in silico models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I½ + Type II and Type I + Type II. Predictions were validated in vitro in AML cell lines and patient samples, with synergy verified by the Loewe Additivity model. Lifirafenib (Type II) + encorafenib (Type I½) was highly synergistic against both NRAS- and KRAS-mutant lines, while synergy of lifir

SUBMITTER: Jones L 

PROVIDER: S-EPMC12247986 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature