Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas
Menée in vitro et à l'aide d'un modèle murin d'adénocarcinome pulmonaire avec mutation des gènes KRAS/P53, cette étude démontre que l'inhibition conjointe de l'activité de la kinase CDK4 et de l'expression de la kinase RAF1 induit une régression tumorale, puis identifie deux mécanismes de résistance pouvant être contrôlés pharmacologiquement
So far, no targeted therapy has been approved for KRAS mutant tumors. We report that combined genetic inactivation of CDK4 and RAF1 in advanced KRAS/p53 mutant lung tumors leads to effective tumor regression without inducing significant toxicities. In spite of this therapeutic response, CDK4/RAF1-resistant cells appeared. We have identified and pharmacologically validated two independent resistance mechanisms involving hypermethylation of tumor-suppressor genes and activation of the PI3K pathway.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.All data are available in the main text and SI Appendix.