Deconstruction of Oncogenic K-RAS Signaling Reveals Focal Adhesion Kinase as a Novel Therapeutic Target in NSCLC
Technical Report,30 Sep 2014,29 Sep 2015
University of Texas Southwestern Medical Center 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 inhibition of FAK causes cell death specifically in KM lung cancer cells KMLC that are either CDKN2A mutant or p53mutant. Furthermore, we found that pharmacologic inhibition of FAK causes the regression specifically of high-grade mutantKrasCdkn2a null lung cancers in genetically engineered mice. These findings provided the rationale for a multi-institutional Phase II clinical trial using the FAK inhibitor FAKi VS-6063 in KMLC patients PI Dr. Gerber at UT Southwestern Medical Center. This trial has completed accrual and was presented at the 2015 World Lung Conference in Denver. Ongoing work aims at establishing whether 1. FAK is a therapeutic target in KMLC using genetically engineered mice 2. determining the underpinnings of the dependency on FAK both in cultured lung cancer cells and in vivo. In this regards, we found that FAK inhibition impairs the DNA damage response, potentiating the effects of radiotherapy specifically in KMLC cells in vitro and in vivo. This finding provides the rationale to combine radiation therapy to FAKi.