EGFR Regulates the Core Autophagy Protein Beclin 1

Autophagy has been shown to protect against tumor initiation, but its role in tumor progression and chemoresistance remains controversial. Activation of EGF receptor (EGFR), which is frequently mutated in many tumors including non–small cell lung cancer (NSCLC), has been shown to inhibit autophagy, but the mechanisms underlying this regulation and the contribution of EGFR-mediated autophagy suppression to NSCLC progression are unknown. Wei and colleagues found that activation of EGFR via ligand stimulation or oncogenic mutations promoted the interaction of EGFR with Beclin 1, an essential autophagy protein, in NSCLC cells. Formation of this complex occurred independent of mTOR and resulted in modulation of the Beclin 1 interactome; EGFR binding increased the interaction of Beclin 1 with the negative regulators BCL2 and Rubicon and impaired its interaction with the class III phosphoinositide 3-kinase VPS34, resulting in autophagy suppression. In contrast, the EGFR tyrosine kinase inhibitor (TKI) erlotinib induced autophagy in TKI-sensitive, EGFR-mutant NSCLC cells and xenograft tumors by disrupting the EGFR–Beclin 1 complex and reversing these changes in the Beclin 1 interactome. EGFR-mediated regulation of autophagy was dependent on phosphorylation of three tyrosine residues within Beclin 1 in response to EGFR activation, and expression of a phosphomimetic mutant Beclin 1 was sufficient to prevent TKI-driven disruption of the EGFR–Beclin 1 complex and induction of autophagy in EGFR-mutant NSCLC cells. Expression of phosphomimetic Beclin 1 enhanced the growth of NSCLC xenografts, which were characterized by increased proliferation and dedifferentiation, indicative of aggressive tumors, despite increased cell death. In addition, EGFR-dependent Beclin 1 phosphorylation and suppression of autophagy conferred partial resistance to EGFR TKIs in NSCLC tumors. These results suggest that EGFR-mediated Beclin 1 inactivation promotes tumor progression and that autophagy inhibition may limit the response to EGFR TKIs in NSCLC.

Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 2013;154:1269–84.