Abstract
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.
Highlights
The epidermal growth factor receptor (EGFR) is oncogenic receptor tyrosine kinase that is often overexpressed/ overactivated in cancers of epithelial origin, and drugs targeting the tyrosine kinase activity of EGFR have been developed as putative therapeutics to treat suchStudies over the past few years have revealed that EGFR promotes cancer cell survival through mechanisms that are independent of its tyrosine kinase activity[7,8,9]
EGFR tyrosine kinase inhibitors (TKI) often cause growth arrest associated with non-selective, pro-survival autophagy[10,11,12]; loss-of-EGFR protein leads to severe autophagic cell death that could be rescued by a kinase-dead EGFR7, which suggests that the tyrosine kinase-dependent (KD) function of EGFR predominantly regulates cell proliferation, whereas the KID function of EGFR has a major role in promoting cancer cell survival
We investigated the processes of TKI (AEE788)-induced autophagy, and autophagy induced by siRNA-mediated knockdown of EGFR protein on two types of cancer cells
Summary
Studies over the past few years have revealed that EGFR promotes cancer cell survival through mechanisms that are independent of its tyrosine kinase activity[7,8,9]. One important outstanding question regarding KD and KID functions of EGFR is that why TKI induced autophagy is pro-survival whereas loss-of-EGFRinduced autophagy is lethal. Answers to this question may reveal the core mechanism(s) underlying the KID prosurvival function of EGFR and should reveal new targets for the treatment of EGFR-dependent cancers
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