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

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

Proceedings of the National Academy of Sciences of the United States of America (2020-09-12)
Laura Esteban-Burgos, Haiyun Wang, Patricia Nieto, Jie Zheng, Carmen Blanco-Aparicio, Carmen Varela, Gonzalo Gómez-López, Fernando Fernández-García, Manuel Sanclemente, Carmen Guerra, Matthias Drosten, Javier Galán, Eduardo Caleiras, Jorge Martínez-Torrecuadrada, Lluis Fajas, Sheng-Bin Peng, David Santamaría, Monica Musteanu, Mariano Barbacid
要旨

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.

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