Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Mol Oncol. 2012 Feb;6(1):15-26. doi: 10.1016/j.molonc.2011.11.009. Epub 2011 Dec 6.
Epidermal growth factor receptor (EGFR) is a validated target in different human malignancies. EGFR tyrosine kinase inhibitors (TKIs) are known to contribute considerably to the extension of progression-free survival in EGFR-mutant non-small cell lung cancer and monoclonal antibodies (mAbs) targeting EGFR have also improved the efficacy outcomes in KRAS wild-type colorectal cancer. Nevertheless, a significant percentage of lung and colorectal cancer patients do not respond to anti-EGFR agents and secondary resistance after initial benefit is a challenging reality faced by clinicians. Extensive preclinical work on the potential mechanisms of resistance to EGFR inhibitors in different disease settings has guided the development of second-generation irreversible EGFR TKIs, more efficient anti-EGFR mAbs, and combination strategies with agents targeting other receptors and downstream effectors. In order to elucidate the role of the multiple therapeutic strategies under investigation to overcome EGFR inhibitors-resistance, rational drug development based on stringent preclinical data, biomarker validation and proper selection of patients in the ongoing clinical trials are of paramount importance. Preliminary results of clinical trials evaluating these approaches will be discussed in this manuscript, with emphasis on TKIs in lung cancer and mAbs in advanced colorectal cancer.
表皮生长因子受体（EGFR）是多种人类恶性肿瘤的有效靶点。已知 EGFR 酪氨酸激酶抑制剂（TKI）可显著延长 EGFR 突变型非小细胞肺癌的无进展生存期，针对 EGFR 的单克隆抗体（mAb）也改善了 KRAS 野生型结直肠癌的疗效。然而，相当一部分肺癌和结直肠癌患者对抗 EGFR 药物无反应，初始获益后的继发耐药是临床医生面临的挑战。在不同疾病环境中针对 EGFR 抑制剂耐药的潜在机制的广泛临床前研究，指导了第二代不可逆 EGFR TKI、更有效的抗 EGFR mAb 以及与靶向其他受体和下游效应器的药物联合策略的发展。为了阐明正在研究的多种治疗策略在克服 EGFR 抑制剂耐药方面的作用，基于严格的临床前数据、生物标志物验证和对正在进行的临床试验中患者的适当选择进行合理的药物开发至关重要。本文将讨论评估这些方法的临床试验的初步结果，重点是肺癌中的 TKI 和晚期结直肠癌中的 mAb。
