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.

对于靶向疗法，KRAS突变型肺腺癌仍然难以治疗。对KRAS下游效应子（包括MAPK途径和相间CDKs）的遗传询问确定CDK4和RAF1是其遗传失活诱导治疗反应而不会引起不可接受的毒性的唯一靶标。在25％的KRAS / p53驱动的晚期肺肿瘤中，伴随的CDK4失活和RAF1消融阻止了肿瘤的进展并诱导了肿瘤的完全消退，但是，经历了部分消退的那些肿瘤中有相当大的比例保留了CDK4 / RAF1耐药细胞群。这些细胞的表征揭示了两个独立的抗性机制，这牵涉到几种肿瘤抑制物的高甲基化和增加的PI3K活性。重要的是，可以对这些CDK4 / RAF1耐药细胞进行药理控制。