University of Manchester, United Kingdom.
University of Manchester, United Kingdom.
EBioMedicine. 2019 Mar;41:711-716. doi: 10.1016/j.ebiom.2019.02.049. Epub 2019 Mar 7.
KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development. With signs of real progress in this subgroup of unmet need, we anticipate that KRAS mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors (CPI).
KRAS 是最常见的非小细胞肺癌（NSCLC）致癌基因，这是一个分子亚群，其特征是在靶向治疗方法（如法呢基转移酶抑制、下游 MEK 抑制和合成致死筛选）方面历史上令人失望。与 NSCLC 的其他重要突变亚型不同，临床前研究支持这样一种假设，即 KRAS 突变可能容易受到免疫治疗方法的影响，其疗效特别是与 TP53 共突变有关。在这篇综述中，我们详细说明了 KRAS 突变型 NSCLC 之前失败的原因，有证据表明 KRAS 突变是从免疫检查点抑制中获益的遗传标志物，以及新兴的直接 K-Ras 抑制剂，它们将很快在临床开发中与免疫疗法联合使用。随着这一未满足需求亚组的真正进展迹象，我们预计 KRAS 突变型 NSCLC 将是评估小分子和免疫检查点抑制剂（CPI）联合应用的最重要的癌症分子亚型。
