Mechanisms of resistance to EGFR-targeted drugs: lung cancer.
Mechanisms of resistance to EGFR-targeted drugs: lung cancer.
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DOI：
10.1136/esmoopen-2016-000060
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发表时间：
2016
期刊：
影响因子：
7.3
通讯作者：
Ciardiello F
中科院分区：
文献类型：
--
作者：
Morgillo F;Della Corte CM;Fasano M;Ciardiello F
尽管通过引入表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（EGFR-TKI）治疗携带EGFR激活突变的晚期非小细胞肺癌（NSCLC）患者的临床结局有所改善，但由于发生内在或获得性耐药，预后仍然不利。我们回顾了已发表的文献和国际会议的口头和海报介绍摘要，这些会议讨论了在临床前模型和NSCLC患者中发现的EGFR-TKI耐药机制。肺癌的分子异质性在对EGFR靶向抑制剂的内在或获得性耐药的可能机制方面有几个含义。已经描述了对EGFR-TKI的几种耐药机制，如继发突变（T790 M，C797 S）的发生，替代信号传导（Met，HGF，AXL，Hh，IGF-1 R）的激活，下游通路的异常（AKT突变，PTEN缺失），EGFR-TKI介导的凋亡通路受损（BCL 2样11/BIM缺失多态性）和组织学转化。虽然已经确定了一些耐药机制，但需要更多的信息来了解和克服对EGFR-TKI药物的耐药性。所描述的大多数耐药机制是选择预先存在的克隆的结果;因此，研究亚克隆改变对肿瘤生物学产生影响并影响癌症进展的机制对于确定最佳治疗策略至关重要。
Despite the improvement in clinical outcomes derived by the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumours harbour EGFR-activating mutations, prognosis remains unfavourable because of the occurrence of either intrinsic or acquired resistance. We reviewed the published literature and abstracts of oral and poster presentations from international conferences addressing EGFR-TKIs resistance mechanisms discovered in preclinical models and in patients with NSCLC. The molecular heterogeneity of lung cancer has several implications in terms of possible mechanisms of either intrinsic or acquired resistance to EGFR-targeted inhibitors. Several mechanisms of resistance have been described to EGFR-TKIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AKT mutations, loss of PTEN), the impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation. Although some of the mechanisms of resistance have been identified, much additional information is needed to understand and overcome resistance to EGFR-TKI agents. The majority of resistance mechanisms described are the result of a selection of pre-existing clones; thus, studies on the mechanisms by which subclonal alterations have an impact on tumour biology and influence cancer progression are extremely important in order to define the best treatment strategy.