Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain.
School of Life Sciences and Technology, Tongji University, 200092 Shanghai, China.
Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24415-24426. doi: 10.1073/pnas.2002520117. Epub 2020 Sep 10.
KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.
KRAS 突变型肺腺癌仍然对靶向治疗具有抗性。对 KRAS 下游效应物（包括 MAPK 通路和间期 CDK）的遗传研究表明，只有 CDK4 和 RAF1 是唯一的靶点，其遗传失活可诱导治疗反应而不会引起不可接受的毒性。同时抑制 CDK4 和 RAF1 可阻止肿瘤进展，并使 25%的 KRAS/p53 驱动的晚期肺肿瘤完全消退，但有相当比例的部分消退的肿瘤仍保留了一部分 CDK4/RAF1 耐药细胞。对这些细胞的特征分析揭示了两种独立的耐药机制，涉及多个肿瘤抑制因子的高甲基化和 PI3K 活性增加。重要的是，这些 CDK4/RAF1 耐药细胞可以通过药理学方法进行控制。这些研究为治疗 KRAS 突变型肺癌（包括耐药肿瘤）开辟了新的治疗策略。
