Abstract: The KRAS mutation is present in approximately 20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in NSCLC and confers resistance to standard anticancer treatment drugs, including EGFR tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between CDK4 downregulation and the KRAS mutation to deliver micellar nanoparticles containing siRNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLC harboring the oncogenic KRAS mutation. Following MNPsiCDK4administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLC. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLC via a synthetic lethal interaction between KRAS and CDK4.

http://dx.doi.org/10.1038/mt.2014.18

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