biostudies-literatureUnknownJones LNHLBI NIH HHSNCI NIH HHSMutations 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 <i>RAS</i>-mutant AML. Our <i>in silico</i> models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I½ + Type II and Type I + Type II. Predictions were validated <i>in vitro</i> 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 <i>NRAS</i>- and <i>KRAS</i>-mutant lines, while synergy of lifirbioRxiv : the preprint server for biology2025.04.29.651188https://www.ebi.ac.uk/biostudies/studies/S-EPMC12247986biostudies-literatureA structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.PMC12247986R01 HL171773R01 CA244660Bond JCarmody CWynne KDias TKholodenko BNJones LImoto HRukhlenko OfalseA structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.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 <i>RAS</i>-mutant AML. Our <i>in silico</i> models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I½ + Type II and Type I + Type II. Predictions were validated <i>in vitro</i> 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 <i>NRAS</i>- and <i>KRAS</i>-mutant lines, while synergy of lifir2025-01-01T00:00:00Z2025 May2025-08-23T03:09:09.017Z2025-08-23T03:09:09.017ZS-EPMC122479864065485010.1101/2025.04.29.651188