Concurrent AXL Inhibition Enhances RAS and ERK Inhibitor Efficacy in KRAS -mutant Pancreatic and Lung Cancer
Year: 2026
Type: preprint
Abstract: 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 SIGNIFICANCE 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.
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
Institutions: Humboldt-Universität zu Berlin, Charité – Universitätsmedizin Berlin, Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, Michigan State University, German Cancer Research Center, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, University of Cincinnati, George Mason University, University of Helsinki, Institute for Molecular Medicine Finland, Navarre Institute of Health Research, Revolution Medicines (United States), University of Copenhagen, Novo Nordisk Foundation, Centro de Investigación Biomédica en Red de Cáncer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Defense, American Cancer Society, Pancreatic Cancer Action Network, Ohio Cancer Research, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Deutschen Konsortium für Translationale Krebsforschung, University of Texas MD Anderson Cancer Center, Agencia Estatal de Investigación, National Cancer Institute
Awards: G1319661684, G1625620992, G2176912741, FOR 5628: MultiskalenMRElastographie bei Krebs zur Erforschung der mechanischen Nische der Tumorbildung und Metastasierung für eine verbesserte Tumordiagnostik, G2477575768, Defining RAS isoform- and mutation-specific roles in oncogenesis, G3666016768, G3823902844, G3974776075, Targeting undruggable RAS for cancer treatment, Integrated Training in Cancer Model Systems, TARGETING KRAS-DYSREGULATED METABOLISM FOR NOVEL THERAPEUTIC APPROACHES, G5216334326, G5944743545, Overcoming resistance to KRASG12D inhibitors in KRASG12D mutant pancreatic cancer, Defining the contributions of WT RAS in RAS-mutant lung cancer, G7187199278, TARGETING KRAS-DYSREGULATED METABOLISM FOR NOVEL THERAPEUTIC APPROACHES, Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer, Divergent Roles of MerTK,Tyro3, and Axl in Pancreatic Cancer and Metastasis, Selective Targeting of Pancreatic Cancer SPORE, Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers, G952828462
OpenAlex ID: W7202199272