Concurrent AXL inhibition enhances RAS and ERK inhibitor efficacy in KRAS-mutant pancreatic and lung cancer

Ching, Y. M.; Narayanan, S.; Klomp, J. A.; Isermann, T.; Loewe, S.; Chang, W.-H.; Waters, A. M.; Nicewarner Pena, S. R.; Baldelli, E.; Edwards, A. C.; Bording, T.; Yang, R.; Goodwin, C. M.; Gautam, P.; Ponz-Sarvise, M.; Horst, D.; Seamon, K.; Zhuang, Y.; Tran, L.; Jiang, J.; Singh, M.; Wennerberg, K.; Petricoin, E. F.; Bryant, K. L.; Stalnecker, C. A.; Earp, H. S.; Cox, A. D.; Sers, C.; Vicent, S.; Der, C. J.; Papke, B.

doi:10.64898/2026.08.10.743026

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bioRxiv · 10.64898/2026.08.10.743026

Concurrent AXL inhibition enhances RAS and ERK inhibitor efficacy in KRAS-mutant pancreatic and lung cancer

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Abstract

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 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. STATEMENT OF SIGNIFICANCEOur 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 KRAS-mutant cancer by maximally inhibiting oncogenic RAS signaling.

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Ching, Y. M., Narayanan, S., Klomp, J. A., Isermann, T., Loewe, S., Chang, W.-H., Waters, A. M., Nicewarner Pena, S. R., Baldelli, E., Edwards, A. C., Bording, T., Yang, R., Goodwin, C. M., Gautam, P., Ponz-Sarvise, M., Horst, D., Seamon, K., Zhuang, Y., Tran, L., Jiang, J., Singh, M., Wennerberg, K., Petricoin, E. F., Bryant, K. L., Stalnecker, C. A., Earp, H. S., Cox, A. D., Sers, C., Vicent, S., Der, C. J., Papke, B.. 2026-08-11. Concurrent AXL inhibition enhances RAS and ERK inhibitor efficacy in KRAS-mutant pancreatic and lung cancer. https://doi.org/10.64898/2026.08.10.743026

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