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Deconstruction of Oncogenic K-RAS Signaling Reveals Focal Adhesion Kinase as a Novel Therapeutic Target in NSCLC

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Technical Report,30 Sep 2012,29 Sep 2016

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University of Texas Dallas United States

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About 25 of lung adenocarcinomas express mutant KRAS KM often is association with co-occurring mutations that inactivate the CDKN2A locus, which comprises p16INK4A and p14ARF, or the p53 tumor suppressors. These mutations contribute to disease progression. There are no therapies that target cancers that express mutant KRAS. Thus, it is notable that with this grant we found that 1. Silencing, pharmacologic inhibition or genetic ablation of FAK causes cell death specifically in KM lung cancer cells KMLC that are either CDKN2A or p53 mutant 2. pharmacologic inhibition of FAK causes the regression specifically of high-grade mutant KrasCdkn2a null lung cancers in genetically engineered mice 3. Genetic ablation of FAK in mouse models of KMLC significantly impairs KM growth 4. FAK silencing, ablation of pharmacologic inhibition impairs the DNA damage response, potentiating the toxic effects of ionizing radiation in preclinical lung cancer models 5. The SUMO E3 ligase PIAS1 interacts with FAK, promoting its nuclear translocation, oncogenic properties and DNA repair activity. These findings provided the rationale for a multi-center Phase II clinical trial using the FAK inhibitor FAKi VS-6063 in KMLC patients PI Dr. Gerber at UT Southwestern Medical Center. Taken together these data support the conclusion that FAK is a therapeutic target in KMLC.

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  • Medicine and Medical Research

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