EGFR-Mediated Beclin 1 Phosphorylation in Autophagy Suppression, Tumor Progression, and Tumor Chemoresistance
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant la phosphorylation de la protéine Becline 1 impliquée dans l'autophagie, la tyrosine kinase EGFR contribue à la progression et à la résistance thérapeutique d'un carcinome du poumon non à petites cellules présentant des mutations activant EGFR
Cell surface growth factor receptors couple environmental cues to the regulation of cytoplasmic homeostatic processes, including autophagy, and aberrant activation of such receptors is a common feature of human malignancies. Here, we defined the molecular basis by which the epidermal growth factor receptor (EGFR) tyrosine kinase regulates autophagy. Active EGFR binds the autophagy protein Beclin 1, leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased Beclin 1-associated VPS34 kinase activity. EGFR tyrosine kinase inhibitor (TKI) therapy disrupts Beclin 1 tyrosine phosphorylation and binding to its inhibitors and restores autophagy in non-small-cell lung carcinoma (NSCLC) cells with a TKI-sensitive EGFR mutation. In NSCLC tumor xenografts, the expression of a tyrosine phosphomimetic Beclin 1 mutant leads to reduced autophagy, enhanced tumor growth, tumor dedifferentiation, and resistance to TKI therapy. Thus, oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery, which may contribute to tumor progression and chemoresistance. "EGFR negatively regulates autophagy by binding to Beclin 1 "Active EGFR phosphorylates Beclin 1 and alters its interactome "EGFR suppression of Beclin 1 may contribute to tumor progression in lung cancer "Lung cancer responses to EGFR inhibitors may involve activation of Beclin 1 The oncogenic receptor tyrosine kinase EGFR regulates the core autophagy machinery by phosphorylating the autophagy protein Beclin 1. This regulation may contribute to the progression and chemoresistance of non-small-cell lung carcinoma with active EGFR mutations.