Lung-Cancer Chemoprevention by Induction of Synthetic Lethality in Mutant KRAS Premalignant Cells In Vitro and In Vivo
Lung-Cancer Chemoprevention by Induction of Synthetic Lethality in Mutant KRAS Premalignant Cells In Vitro and In Vivo
复制标题
DOI：
10.1158/1940-6207.capr-10-0235
复制
发表时间：
2011-05-01
影响因子：
3.3
通讯作者：
Wu, Xiangwei
中科院分区：
文献类型：
--
作者：
Huang, Shaoyi;Ren, Xiaoyang;Wu, Xiangwei
肺癌是美国男性和女性癌症死亡的主要原因，尽管治疗策略有所改进，但5年生存率很低。这些数据强调了有效的化学预防这种癌症的巨大需要。KRAS的突变和激活在腺癌亚型的非小细胞肺癌(NSCLC)中频繁发生，并被认为是其发展的主要驱动因素。在这项研究中，我们开发了一种新的化学预防非小细胞肺癌的方法，包括对突变的KRAS细胞进行特异性的凋亡靶点。这一方法是基于caspase SMAC/Diablo的第二个线粒体激活物-肿瘤坏死因子相关的凋亡诱导配体(TRAIL)和KRAS之间的人工致死相互作用。KRAS的突变激活通过上调死亡受体和下调诱骗受体来调节TRAIL受体的表达。此外，致癌的KRAS通过激活ERK/丝裂原活化蛋白激酶(MAPK)介导的c-Myc，抑制细胞FADD样白介素1β转换酶(FLICE)样抑制蛋白(c-FliP)的表达。Smac通过拮抗X连锁的凋亡抑制蛋白(XIAP)，克服了KRAS诱导的细胞存活信号。因此，TRAIL与模拟Smac的小分子结合可特异性地诱导突变的KRAS细胞发生凋亡，而不会损伤正常细胞。我们进一步表明，在KRAS诱导的小鼠肺癌模型中，TRAIL和Smac的短期间歇体内治疗模拟了诱导肿瘤细胞凋亡和减轻肿瘤负担的作用。这些结果反映了选择性治疗方法在非小细胞肺癌化学预防中的潜在益处。癌症猎物；4(5)；666-73。(C)2011年AACR。
Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of KRAS occur frequently in, and are thought to be a primary driver of the development of, non-small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant KRAS cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and KRAS. Mutational activation of KRAS modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic KRAS repressed cellular FADD-like interleukin 1 beta-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame KRAS-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant KRAS cells without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC. Cancer Prey Res; 4(5); 666-73. (c) 2011 AACR.