| Literature DB >> 32913049 |
Laura Esteban-Burgos1, Haiyun Wang2, Patricia Nieto1, Jie Zheng2, Carmen Blanco-Aparicio3, Carmen Varela4, Gonzalo Gómez-López5, Fernando Fernández-García1, Manuel Sanclemente1, Carmen Guerra1, Matthias Drosten1, Javier Galán1, Eduardo Caleiras6, Jorge Martínez-Torrecuadrada7, Lluis Fajas8, Sheng-Bin Peng9, David Santamaría1, Monica Musteanu10, Mariano Barbacid10.
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.Entities:
Keywords: CDK4/RAF1 inhibition; KRAS; Lung Cancer; Resistance Mechanisms; Tumor Regression
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Year: 2020 PMID： 32913049 PMCID： PMC7533841 DOI： 10.1073/pnas.2002520117
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205