Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas

L Esteban-Burgos, H Wang, P Nieto… - Proceedings of the …, 2020 - National Acad Sciences
L Esteban-Burgos, H Wang, P Nieto, J Zheng, C Blanco-Aparicio, C Varela, G Gómez-López
Proceedings of the National Academy of Sciences, 2020National Acad Sciences
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 …
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.
National Acad Sciences