Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Cancer Lett. 2017 Jun 28;396:94-102. doi: 10.1016/j.canlet.2017.03.023. Epub 2017 Mar 18.
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.
表皮生长因子受体（EGFR）及其相关途径是 CRC 发展和进展的关键调节因子。针对 EGFR 的单克隆抗体（MoAbs）西妥昔单抗和帕尼单抗，在转移性结直肠癌（mCRC）的治疗方面取得了重大进展，在几项临床试验中，无进展生存期和总生存期都有所改善。然而，抗 EGFR MoAbs 的活性似乎仅限于 mCRC 的一部分患者。研究强调，抗 EGFR MoAbs 的获得性耐药在生化上趋于集中到 Ras/Raf/Mek/Erk 和 PI3K/Akt/mTOR 途径。最近的数据还表明，抗 EGFR MoAbs 的获得性耐药伴随着 EGFR 内化、泛素化、降解和延长下调的抑制。众所周知，自噬是一种自我吞噬的过程，被认为与抗 EGFR MoAbs 治疗的耐药性有关。此外，抗 EGFR MoAbs 诱导的自噬在癌细胞中作为一种保护反应。因此，在用 EGFR MoAbs 治疗后抑制自噬可能会导致自噬细胞死亡。包含抗 EGFR MoAbs 和自噬抑制剂的联合治疗将代表一种多管齐下的方法，可以演变成 mCRC 患者的积极治疗策略。
