摘要
非小细胞肺癌是最常见的肺癌,最常见的基因突变是EGFR突变,EGFR-TKI已被用于治疗含这类突变的患者。然而,随着治疗进展,患者逐渐出现耐药性导致治疗失败。主要原因是EGFR信号通路下游重新激活,其中RAS/RAF/MEK/ERK和PI3K/AKT/PKC途径最重要。ERK1/2信号再激活可产生对EGFR抑制剂的抗性。目前临床研究已经发现,MEK抑制剂可以抑制ERK磷酸化,从而阻止随后的MAP激酶下游磷酸化,并因此诱导肿瘤活动的退化和停滞。大量试验表明,ERK途径的持续激活有助于获得吉非替尼耐药性。MEK抑制剂还可以诱导细胞周期阻滞和凋亡。本文总结了MEK抑制剂和EGFR-TKI的作用及其在NSCLC治疗中的作用,为肺癌分子靶向治疗提供了新思路。
Non-small cell lung cancer（ NSCLC）,the most common lung cancer,takes away the lives of many people all over the world every year. The most common gene mutation in non-small cell lung cancer is EGFR mutations,and EGFR-TKIs have been targeted for such mutations,such as gefitinib. However,with the progress of treatment,NSCLC patients have developed the TKI resistance,leading to treatment failure. The main reason is that the downstream of the EGFR signaling pathway is re-activated,in which RAS/RAF/MEK/ERK and PI3 K/AKT/PKC pathway are the most important. Persistence or reactivation of ERK1/2 signaling can produce resistance to EGFR inhibitors. Present clinical studies have found that MEK inhibitors not only can inhibit ERK phosphorylation levels to prevent the subsequent downstream phosphorylation and activation of MAP kinase and consequently induce tumor regression and/or stasis in some contexts,but also show some anti-tumor activity. A number of trials have shown that the continuous activation of the ERK pathway contributes to the acquisition of gefitinib resistance,so combining MEK inhibitors with EGFR-TKIs can overcome the resistance of acquired TKI resistant cells to TKIs and reduce resistance.MEK inhibitors can not only inhibit MEK signaling pathway,but also induce cell cycle arrest and apoptosis to inhibit the growth of some NSCLC cells tumor cell autophagy. Furthermore,MEK inhibitors can reverse the resistance to BV,which is beneficial in combination therapy with TKI and BV. This review summarizes the role of MEK inhibitors and EGFR-TKIs respectively and the combination of the both in NSCLC treatment in detail and offer novel insights into molecular targeting therapy for lung cancer.
作者
娄芮
曹海霞
李洋
董书辰
李惠子
杜沅原
吴建中
冯继锋
Lou Rui;Cao Haixia;Li Yang;Dong Shuchen;Li Huizi;Du Yuanyuan;Wu Jianzhong;Feng Jifeng(Jiangsu Cancer Hospital ＆ Jiangsu Institute of Cancer Research ＆ The Affiliated Cancer Hospital of Nanjing Medical University,Jiangsu Nanjing 210000,China.)
出处
《现代肿瘤医学》
CAS
2018年第17期2785-2789,共5页
Journal of Modern Oncology
基金
国家自然科学基金(编号:81372396)
江苏省自然科学基金(编号:BK20141016)
