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

Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain.
Cancer cell (Impact Factor: 23.52). 07/2010; 18(1):63-73. DOI: 10.1016/j.ccr.2010.05.025
Source: PubMed


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.

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    • "In calu-6 lung xenograft tumors, LY2835219 can be combined with gemcitabine resulting in additive antitumor activity and inhibition of RRM1 in the absence of a cell cycle arrest. These results indicate that the antitumor activity of CDK4/6 inhibitors can be context-sensitive, as previously reported in genetically engineered mouse models for glioma and lung cancer [47, 48]. In addition to its broad antitumor activity, LY2835219 has several additional desirable properties. "
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    • "Likewise, cyclin D1, NF-kB, and Myc are necessary for Ras tumorigenesis; further analysis of the role of these pathways may lead to new therapeutic insights . For example, Puyol et al. (2010) recently demonstrated that germline or conditional deletion of Cdk4 led to senescence in lung cells expressing activated K-Ras. Furthermore, treatment with a Cdk4 inhibitor reduced the growth of K-Ras-driven tumors . "
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    • "In addition to genetic aberrations within the RB pathway, several oncogenic signals contribute to cell cycle deregulation and E2F activity. Oncogenic KRAS (amplified in 11% of HGSOC), MYC, and receptor tyrosine kinases (RTK) all converge on cyclin D and require its function for their oncogenic activity (92–94). Moreover, a synthetic lethal relationship was described for KRAS and CDK4, the binding partner of cyclin D (94). "
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