{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Jones L"],"funding":["NHLBI NIH HHS","NCI NIH HHS"],"pubmed_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 <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 lifir"],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2025.04.29.651188"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12247986"],"repository":["biostudies-literature"],"pubmed_title":["A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia."],"pmcid":["PMC12247986"],"funding_grant_id":["R01 HL171773","R01 CA244660"],"pubmed_authors":["Bond J","Carmody C","Wynne K","Dias T","Kholodenko BN","Jones L","Imoto H","Rukhlenko O"],"additional_accession":[]},"is_claimable":false,"name":"A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.","description":"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 lifir","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2025-08-23T03:09:09.017Z","creation":"2025-08-23T03:09:09.017Z"},"accession":"S-EPMC12247986","cross_references":{"pubmed":["40654850"],"doi":["10.1101/2025.04.29.651188"]}}