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

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 cancer...

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Bibliographic Details
Main Author: Scaglioni,Pier P
Format: Report
Language:English
Subjects:
cells(biology)
FAK(focal adhesion kinase)
genes
in vitro analysis
inhibitors
KRAS
lung cancer
mice
mouse lung cancer models
neoplasms
PHARMACOLOGIC ACTIONS
preclinical studies
radiosensitization
radiotherapy
RNAi
targeted kinase inhibitors
therapeutics
transgenic mice
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Summary: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 mutantKras;Cdkn2a 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.