The oncogenic epidermal growth factor receptor (EGFR) is commonly overexpressed in solid cancers. The tyrosine kinase activity of EGFR has been a major therapeutic target for cancer; however, the efficacy of EGFR tyrosine kinase inhibitors to treat cancers has been challenged by innate and acquired resistance at the clinic. Accumulating evidence suggests that EGFR possesses kinase-independent pro-survival functions, and that cancer cells are more vulnerable to reduction of EGFR protein than to inhibition of its kinase activity. The molecular mechanism underlying loss-of-EGFR-induced cell death remains largely unknown. In this study, we show that, unlike inhibiting EGFR kinase activity that is known to induce pro-survival non-selective autophagy, downregulating EGFR protein, either by siRNA, or by a synthetic EGFR-downregulating peptide (Herdegradin), kills prostate and ovarian cancer cells via selective mitophagy by activating the mTORC2/Akt axis. Furthermore, Herdegradin induced mitophagy and inhibited the growth of orthotopic ovarian cancers in mice. This study identifies anti-mitophagy as a kinase-independent function of EGFR, reveals a novel function of mTORC2/Akt axis in promoting mitophagy in cancer cells, and offers a novel approach for pharmacological downregulation of EGFR protein as a potential treatment for EGFR-positive cancers.
Oncogenesis. 2018 Jan 23*** epublish ***
Rajasekhara Reddy Katreddy, Lakshmi Reddy Bollu, Fei Su, Na Xian, Shivangi Srivastava, Rintu Thomas, Yubing Dai, Bing Wu, Yunlu Xu, Michael A Rea, James M Briggs, Qingyuan Zhang, Xiongbin Lu, Gangxiong Huang, Zhang Weihua
Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Immunotherapy Institute, Fujian Medical University, University Town, Fuzhou, Fujian, 350122, China., Department of Medical Oncology, Cancer Hospital of Harbin Medical University, Harbin Medical University, 150081, Harbin, Heilongjiang, China., Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Immunotherapy Institute, Fujian Medical University, University Town, Fuzhou, Fujian, 350122, China. ., Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA. .