ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer
Menée à l'aide de données du projet "The Cancer Genome Atlas" ainsi que de lignées cellulaires, d'échantillons tumoraux et d'échantillons tissulaires adjacents issus de patients atteints d'un cancer du poumon non à petites cellules, cette étude met en évidence un mécanisme par lequel la palmitoyltransférase ZDHHC11, via la palmytilation de la protéine AXL, contribue à la résistance des cellules cancéreuses à l'osimertinib
Resistance to osimertinib remains a major challenge in epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC), with approximately 40 to 50% of cases lacking identifiable genotypic alterations. Our study provides a potential pathway for exploring the role of palmitoylation in targeted therapy resistance and highlight a critical role for ZDHHC11-mediated AXL palmitoylation in resistance to osimertinib treatment. These findings provide mechanistic insights into the antitumor efficacy of tyrosine kinase inhibitors, identify ZDHHC11 as a potential therapeutic target for improving response to osimertinib in NSCLC patients with high ZDHHC11 expression, providing a mechanistic basis for future clinical exploration. 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.
Proceedings of the National Academy of Sciences , article en libre accès, 2025