A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma

Marta Puyol, Alberto Martín, Pierre Dubus, Francisca Mulero, Pilar Pizcueta, Gulfaraz Khan, Carmen Guerra, David Santamaría, Mariano Barbacid

Research output: Contribution to journalArticlepeer-review

331 Citations (Scopus)

Abstract

We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes.

Original languageEnglish
Pages (from-to)63-73
Number of pages11
JournalCancer Cell
Volume18
Issue number1
DOIs
Publication statusPublished - Jul 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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