Concurrent AXL Inhibition Enhances RAS and ERK Inhibitor Efficacy in KRAS -mutant Pancreatic and Lung Cancer.

Authors

Yan Ming Ching, Shruthi Narayanan, Jeffrey A Klomp, Tamara Isermann, Sina Loewe, Wen-Hsuan Chang, Andrew M Waters, Sheila R Nicewarner Peña, Elisa Baldelli, A Cole Edwards, Teresa Börding, Runying Yang, Craig M Goodwin, Prson Gautam, Mariano Ponz-Sarvisé, David Horst, Kyle Seamon, Yongxian Zhuang, Linh Tran, Jingjing Jiang, Mallika Singh, Krister Wennerberg, Emanuel F Petricoin, Kirsten L Bryant, Clint A Stalnecker, H Shelton Earp, Adrienne D Cox, Christine Sers, Silvestre Vicent, Channing J Der, Bjoern Papke

Published in

bioRxiv : the preprint server for biology. Aug 11, 2026. Epub Aug 11, 2026.

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.
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 KRAS -mutant cancer by maximally inhibiting oncogenic RAS signaling.

PMID:
42845417
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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