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AXL phosphosite mapping links FAK1 and YAP1 signaling to erlotinib resistance in EGFR-mutant lung cancer

Year: 2026
Type: article
Abstract: Targeted therapies for receptor tyrosine kinases are effective but invariably limited by drug resistance. In EGFR-mutant lung cancer, AXL activation drives resistance to erlotinib by restoring cell survival and migration. To map these signaling mechanisms, we generated a panel of lung adenocarcinoma PC9 cell lines with phenylalanine substitutions at each intracellular AXL tyrosine residue. By integrating phosphorylation data with phenotypic changes via multivariate modeling, we found that AXL signaling organizes into two clusters enriched for Abl1 and SFK substrate motifs. A peptide specificity screen identified FAK1 as a top proximal substrate of AXL. Downstream, AXL-mediated YAP1 activation was found to sustain drug tolerance, while combined inhibition eliminated persister cells in vitro. These AXL and YAP pathways correlate with disease progression and poor clinical outcomes in erlotinib-treated patients. Collectively, this study dissects the specific signaling regulators by which AXL drives erlotinib resistance.
Source: Cell Reports
DOI: 10.1016/j.celrep.2026.117717
Authors: Marc Creixell, Scott D. Taylor, Jacqueline Gerritsen, Mingxuan Jiang, Song Yi Bae, Teresa Augustin, Michelle Loui, Carmen Boixo, Saki Minamino, Victoria Gong, Pau Creixell, Forest M. White, Aaron S. Meyer
Institutions: University of California, Los Angeles, UCLA Jonsson Comprehensive Cancer Center, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, University of Cambridge, Cancer Research UK, Cancer Research UK Cambridge Center
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W7169753241
FWCI:
Cites: 76
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Related to: 10