Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Prev Res (Phila). 2011 May;4(5):666-73. doi: 10.1158/1940-6207.CAPR-10-0235.
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 1β-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.
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善，但 5 年生存率仍然很低。这些数据突出表明，非常需要有效的这种癌症化学预防。KRAS 突变和激活经常发生在非小细胞肺癌（NSCLC）的腺癌亚型中，并被认为是该癌症发展的主要驱动因素。在这项研究中，我们开发了一种新的 NSCLC 化学预防方法，涉及突变型 KRAS 细胞凋亡的特异性靶向。这种方法基于 TNF 相关凋亡诱导配体（TRAIL）、第二线粒体衍生的半胱天冬酶激活物 Smac/DIABLO（Smac）和 KRAS 之间的合成致死相互作用。KRAS 的突变激活通过上调死亡受体和下调诱饵受体来调节 TRAIL 受体的表达。此外，致癌 KRAS 通过激活 Erk/丝裂原活化蛋白激酶（MAPK）介导的 c-Myc 激活来抑制细胞 FADD 样白细胞介素 1β转化酶（FLICE）样抑制蛋白（c-FLIP）的表达。Smac 通过拮抗 X 连锁凋亡抑制蛋白（XIAP）克服了 KRAS 诱导的细胞存活信号。因此，TRAIL 和 Smac 小分子模拟物的组合特异性诱导突变型 KRAS 细胞凋亡，而不会伤害正常细胞。我们进一步表明，TRAIL 和 Smac 模拟物的短期、间歇性体内治疗可诱导肿瘤细胞凋亡，并减少 KRAS 诱导的肺癌小鼠模型中的肿瘤负担。这些结果反映了针对 NSCLC 化学预防的选择性治疗方法的潜在益处。
