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

Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24415-24426. doi: 10.1073/pnas.2002520117. Epub 2020 Sep 10.


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.

Keywords: CDK4/RAF1 inhibition; KRAS; Lung Cancer; Resistance Mechanisms; Tumor Regression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / genetics*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Gene Silencing
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Proto-Oncogene Proteins c-raf / genetics*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Antineoplastic Agents
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)