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

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. ► Ablation of Cdk4 induces a senescence response in cells expressing a K- Ras oncogene ► This synthetic lethal interaction is exquisitely specific for lung cells ► Loss of Cdk4 prevents progression of advanced CT+ lung adenocarcinomas ► A selective CDK4 inhibitor has significant therapeutic activity against these tumors