Y. M. Ching, S. Narayanan, J. A. Klomp, T. Isermann, S. Loewe, W.-H. Chang, A. M. Waters, S. R. Nicewarner Pena, E. Baldelli, A. C. Edwards, T. Bording, R. Yang, C. M. Goodwin, P. Gautam, M. Ponz-Sarvise, D. Horst, K. Seamon, Y. Zhuang, L. Tran, J. Jiang, M. Singh, K. Wennerberg, E. F. Petricoin, K. L. Bryant, C. A. Stalnecker, H. S. Earp, A. D. Cox, C. Sers, S. Vicent, C. J. Der, B. Papke
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 significantly enhanced growth suppression in human KRAS-mutant pancreatic and lung cancer models. Combined AXLi and RASi treatment of human KRAS-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.