Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer
Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer
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DOI：
10.3748/wjg.v22.i28.6345
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发表时间：
2016-07-28
影响因子：
4.3
通讯作者：
Troiani, Teresa
中科院分区：
文献类型：
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作者：
Sforza, Vincenzo;Martinelli, Erika;Troiani, Teresa
尽管过去 20 年来观察到的治疗方法取得了令人瞩目的进步，通过引入活性化疗药物和靶向药物，中位总生存期从仅采用最佳支持治疗的 6 个月延长至大约 30 个月，但转移性结直肠癌 (mCRC) 患者的预后仍然很差。鉴于在多个阶段观察到的无进展生存期、总生存期、缓解率和生活质量方面的相关疗效，针对表皮生长因子受体（EGFR）的单克隆抗体（moAb）西妥昔单抗和帕尼单抗无疑代表了转移性结直肠癌治疗的重大进步。不同治疗方案之间的临床试验。然而，抗 EGFR 单克隆抗体仅对一小部分患者有效。例如，KRAS 和 NRAS 突变已被确定为这些药物耐药性的生物标志物，从而改善了可能从这些治疗中受益的患者的选择。然而，其他一些改变可能会影响对这些药物的反应，不幸的是，即使是反应者最终也会在大约 13-18 个月内产生继发性（或获得性）耐药性，从而产生耐药性。几项研究强调，抗 EGFR 药物的原发性和获得性耐药性的负责任的改变在生物化学上汇聚到 MEK-ERK 和 PIK3CA-AKT 途径。在这篇综述中，我们描述了目前已知的抗 EGFR 单克隆抗体的原发性和获得性耐药机制，以及为预防、克服或恢复这些耐药性而评估的各种策略。
The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase. clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.