Concurrent AXL Inhibition Enhances RAS and ERK Inhibitor Efficacy in <i>KRAS</i> -mutant Pancreatic and Lung Cancer

<jats:title>ABSTRACT</jats:title> <jats:p> Resistance limits the clinical efficacy of RAS inhibitors. We applied chemical and genetic screens and identified the AXL receptor tyrosine kinase as a driver of resistance to RAS-ERK inhibition. We determined that combination treatment with the AXL inhibitor bemcentinib (AXLi) together with the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 (RASi) or the ERK-selective inhibitor SCH772984 (ERKi) significantly enhanced growth suppression in human <jats:italic>KRAS</jats:italic> -mutant pancreatic and lung cancer models. Combined AXLi and RASi treatment of human <jats:italic>KRAS</jats:italic> -mutant pancreatic cell line−derived xenograft tumors synergistically suppressed ERK activation and MYC expression, and caused tumor regression. Analyses of immunocompetent mouse allograft pancreatic tumor models revealed a largely tumor cell−intrinsic response to inhibitor treatment. We identified an unexpected mechanism whereby KRAS inhibition upregulated the AXL ligand GAS6, activating AXL but inducing an AXL-dependent adaptive resistance mechanism wherein AXL antagonizes RASi efficacy. Our observations support concurrent AXL inhibition as a strategy to enhance RAS inhibitor clinical efficacy. </jats:p> <jats:sec> <jats:title>STATEMENT OF SIGNIFICANCE</jats:title> <jats:p> Our findings identify AXL as a driver of resistance to RAS inhibitors, establishing a combination strategy to overcome resistance and enhance RAS inhibitor therapeutic efficacy in <jats:italic>KRAS</jats:italic> -mutant cancer by maximally inhibiting oncogenic RAS signaling. </jats:p> </jats:sec>