Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer. (28th June 2017)

• Record Type: Journal Article
• Authors: Koustas, Evangelos; Karamouzis, Michalis V.; Mihailidou, Chrysovalantou; Schizas, Dimitrios; Papavassiliou, Athanasios G.
• Is Part Of: Cancer letters. Volume 396(2017)
• Page Start: 94
• Page End: 102
• Publication Date: 2017-06-28
• Subjects: Colorectal cancer -- Epidermal growth factor receptor -- Autophagy -- Endocytosis -- Panitumumab -- Cetuximab; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.03.023
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways. Recent data also suggest that acquired-resistance to anti-EGFR MoAbs is accompanied by inhibition of EGFR internalization, ubiqutinization, degradation and prolonged downregulation. It is well established that autophagy, a self-cannibalization process, is considered to be associated with resistance to the anti-EGFR MoAbs therapy. Additionally, autophagy induced by anti-EGFR MoAbs acts as a protective response in cancer cells. Thus, inhibition of autophagy after treatment with EGFR MoAbs can result in autophagic cell death. A combination therapy comprising of anti-EGFR MoAbs and autophagy inhibitors would represent a multi-pronged approach that could be evolved into an active therapeutic strategy in mCRC patients. Highlights: Molecular mechanisms of resistance to anti-EGFR antibodies. Acquired resistance accompanied by inhibition of EGFR internalization and sorting. Anti-EGFR MoAbs can promote autophagy. Targeting autophagy machinery inhibit EGFR trafficking – New therapeutic strategy.