Drug Development Department at Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif.
Department of Respiratory Medicine at Pontchaillou Hospital, Rennes 1 University, Rennes.
Ann Oncol. 2018 Jan 1;29(suppl_1):i28-i37. doi: 10.1093/annonc/mdx705.
Lung cancer represents the leading cause of cancer-related deaths worldwide. Despite great advances in its management with the recent emergence of molecular targeted therapies for non-small-cell lung cancer (NSCLC), relapse of the metastatic disease always occurs within approximately one year. Epidermal growth factor receptor (EGFR) mutant tumours are the prime example of oncogene addiction and clonal evolution in oncology, regarding the emergence of resistance to first- and second-generation EGFR inhibitors. Multiple studies have revealed that the EGFR-T790M gatekeeper mutation is the main cause of tumour escape. Recently, irreversible pyrimidine-based EGFR inhibitors especially designed for this particular setting have shown robust clinical activity. However, similar to first- and second-generation inhibitors, the development of a diversified set of resistance mechanisms in response to these new compounds is an emerging issue. To date, clinical management of this growing number of patients has not been clearly established, even if anecdotal responses to subsequent molecularly guided therapies have been observed. By exhaustively reviewing and classifying all the preclinical and clinical data published on resistance to third-generation EGFR inhibitors in NSCLC, this work reveals the heterogeneity of the mechanisms that a tumour can develop to evade therapeutic pressure. Strategies currently being tested in clinical trials are discussed in light of these findings.
肺癌是全球癌症相关死亡的主要原因。尽管近年来针对非小细胞肺癌（NSCLC）的分子靶向治疗有了很大进展，但转移性疾病的复发仍在大约一年后发生。表皮生长因子受体（EGFR）突变肿瘤是肿瘤学中癌基因成瘾和克隆进化的典型例子，因为其对第一代和第二代 EGFR 抑制剂的耐药性出现。多项研究表明，EGFR-T790M 看门突变是肿瘤逃逸的主要原因。最近，专门针对这种特定情况设计的不可逆嘧啶基 EGFR 抑制剂显示出了强大的临床活性。然而，与第一代和第二代抑制剂一样，针对这些新化合物产生的多样化耐药机制是一个新出现的问题。迄今为止，尽管观察到对后续分子指导治疗的偶发反应，但对越来越多的此类患者的临床管理尚未明确确立。通过详尽地审查和分类所有关于 NSCLC 中第三代 EGFR 抑制剂耐药性的临床前和临床数据，这项工作揭示了肿瘤可以发展出逃避治疗压力的机制的异质性。根据这些发现，讨论了目前正在临床试验中测试的策略。
