Genetics and biomarkers in personalisation of lung cancer treatment
Genetics and biomarkers in personalisation of lung cancer treatment
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DOI：
10.1016/s0140-6736(13)61715-8
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发表时间：
2013-08-24
期刊：
影响因子：
168.9
通讯作者：
Karachaliou, Niki
中科院分区：
文献类型：
--
作者：
Rosell, Rafael;Bivona, Trever G.;Karachaliou, Niki
非小细胞肺癌通常在转移阶段被诊断出来，中位生存期仅为1年。将表皮生长因子受体（EGFR）中的驱动突变鉴定为肺腺癌亚组中的主要致癌事件，从而建立了该疾病的靶向治疗和遗传分析模型。EGFR酪氨酸激酶抑制剂可使60%的患者病情缓解，但缓解时间很短。既存EGFR Thr 790 Met突变可能是导致这些一过性应答的亚克隆驱动因素。AXL过表达和MED 12功能降低是EGFR突变型非小细胞肺癌对酪氨酸激酶抑制剂耐药的标志信号通路之间的串扰是另一种耐药机制;因此，鉴定相关分子组分可能导致开发共同靶向这些分子的联合治疗，而不是EGFR酪氨酸激酶抑制剂单药治疗。此外，新的生物标志物可以通过治疗前和治疗期间的系列重新活检的深度测序分析来鉴定。
Non-small-cell lung cancer is often diagnosed at the metastatic stage, with median survival of just 1 year. The identification of driver mutations in the epidermal growth factor receptor (EGFR) as the primary oncogenic event in a subset of lung adenocarcinomas led to a model of targeted treatment and genetic profiling of the disease. EGFR tyrosine kinase inhibitors confer remission in 60% of patients, but responses are short-lived. The pre-existing EGFR Thr790Met mutation could be a subclonal driver responsible for these transient responses. Overexpression of AXL and reduced MED12 function are hallmarks of resistance to tyrosine kinase inhibitors in EGFR-mutant non-small-cell lung cancer. Crosstalk between signalling pathways is another mechanism of resistance; therefore, identification of the molecular components involved could lead to the development of combination therapies cotargeting these molecules instead of EGFR tyrosine kinase inhibitor monotherapy. Additionally, novel biomarkers could be identified through deep sequencing analysis of serial rebiopsies before and during treatment.