ArticleProceedings of the National Academy of Sciences of the United States of America2025
ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- AXL at the nexus of therapeutic resistance, tumor vascularization, and immune evasion in cancer.iScience · 2026Review
- ABHD17C-Mediated S-Depalmitoylation of BCL6B Enhances CD24 Transcription to Resist Macrophage Phagocytosis in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- [Role of Receptor Tyrosine Kinase AXL in Cancer Targeted Therapy Drug Resistance].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2026Review
- MXRA8, a key palmitoylation-related gene, promotes bladder cancer progression via remodeling tumor microenvironment and predicts poor prognosis.BMC urology · 2026Article
- The Roles of ProteinCancer communications (London, England) · 2026Review
- Advances in understanding the mechanisms underlying acquired resistance to third-generation tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in cell and developmental biology · 2026Review
Corrections and comments
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Authors and funding
10 authors.
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Abstract
Receptor tyrosine kinase pathway rewiring represents a fundamental mechanism underlying acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC). While posttranslational modifications facilitate aberrant activation of bypass signaling networks, the specific contribution of ZDHHC palmitoyl acyltransferase-mediated palmitoylation remains poorly characterized. Here, ZDHHC11-mediated palmitoylation contributes to osimertinib resistance in EGFR-mutant NSCLC. Patient samples, along with in vitro and in vivo functional studies, indicated that ZDHHC11 upregulation reduces the sensitivity of tumor cells to osimertinib by promoting malignant phenotype. Mechanistically, we establish AXL receptor tyrosine kinase as the critical substrate. ZDHHC11 catalyzes AXL palmitoylation at Cys869, inducing plasma membrane retention and constitutive activation. This triggers downstream PI3K-AKT signaling, with AXL knockout alleviating the effect of ZDHHC11-driven resistance. Crucially, pharmacological inhibition ZDHHC11-mediated palmitoylation with the broad-spectrum palmitoylation inhibitor 2-bromopalmitate effectively augmented the antitumor effects of osimertinib. Collectively, ZDHHC11 regulates osimertinib resistance in a palmitoylation-dependent manner. Targeting the ZDHHC11-AXL axis may provide a promising therapeutic strategy for the treatment of osimertinib-resistant EGFR-mutant NSCLC patients with high ZDHHC11 expression.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.