Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas
Laura Esteban-Burgos, Haiyun Wang, Patricia Nieto, Jie Zheng, Carmen Blanco‐Aparicio, Carmen Varela, Gonzalo Goméz-López, Fernando Fernández-García, Manuel Sanclemente, Carmen Guerra, Matthias Drosten, Javier Galán, Eduardo Caleiras, Jorge L. Martı́nez-Torrecuadrada, Lluís Fajas, Sheng-Bin Peng, David Santamarı́a, Mónica Musteanu, Mariano Barbacid
Abstract
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.