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Here, we employ a structure-based, dynamic RAS pathway model to successfully predict RAF inhibitor (RAFi) combinations which synergistically suppress ERK signaling in\n                  <jats:italic>RAS<\/jats:italic>\n                  -mutant AML.\n                <\/jats:p>\n                <jats:p>\n                  Our\n                  <jats:italic>in silico<\/jats:italic>\n                  models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I\u00bd + Type II and Type I + Type II. Predictions were validated\n                  <jats:italic>in vitro<\/jats:italic>\n                  in AML cell lines and patient samples, with synergy verified by the Loewe Additivity model. Lifirafenib (Type II) + encorafenib (Type I\u00bd) was highly synergistic against both\n                  <jats:italic>NRAS<\/jats:italic>\n                  \u2013 and\n                  <jats:italic>KRAS<\/jats:italic>\n                  -mutant lines, while synergy of lifirafenib + SB590885 (Type I) was specific to\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutants. Immunoblotting confirmed that combination efficacy correlated strongly with decreased RAS pathway activation.\n                <\/jats:p>\n                <jats:p>\n                  Leveraging the pharmacokinetic predictions of our\n                  <jats:italic>in silico<\/jats:italic>\n                  model, both combinations were then assessed in a pre-clinical\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutant AML patient-derived xenograft (PDX) model, showing significantly improved leukaemia growth delay and event-free survival compared with single agent approaches. Assessment of leukemia burden in bone marrow and spleen during treatment further showed site-specific efficacy against circulating and spleen-resident blasts for both combinations.\n                <\/jats:p>\n                <jats:p>\n                  In summary, we report that our structure based-modelling approach can effectively identify novel, non-obvious, and well-tolerated RAFi combinations that are highly effective against\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  models, thereby suggesting alternative potential therapeutic strategies for high-risk\n                  <jats:italic>RAS<\/jats:italic>\n                  -mutant AML.\n                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