Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 23, Pages 5851-5863Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-2603
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Funding
- CDMRP LCRP [LC110229]
- American Cancer Society Scholar Award [13-068-01-TBG]
- UT Southwestern Friends of the Comprehensive Cancer Center, Texas
- Science and Technology Program of Guangzhou, China [2012J5100031]
- NCI [1F31CA180689-01, T32CA124334, R01 CA102972]
- Lung Cancer Moonshot Program
- V Foundation Grant
- Ford Petrin Donation
- CCSG Program
- University of Texas Southwestern Medical Center
- University of Texas MD Anderson Cancer Center Lung SPORE [5 P50 CA070907]
- NIH Cancer Center Grant [CA016672, 2P30 CA142543 06]
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Purpose: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide due to the limited availability of effective therapeutic options. For instance, there are no effective strategies for NSCLCs that harbor mutant KRAS, the most commonly mutated oncogene in NSCLC. Thus, our purpose was to make progress toward the generation of a novel therapeutic strategy for NSCLC. Experimental Design: We characterized the effects of suppressing focal adhesion kinase (FAK) byRNA interference (RNAi), CRISPR/CAS9 gene editing or pharmacologic approaches in NSCLC cells and in tumor xenografts. In addition, we tested the effects of suppressing FAK in association with ionizing radiation (IR), a standard-of-care treatment modality. Results: FAK is a critical requirement of mutant KRAS NSCLC cells. With functional experiments, we also found that, in mutant KRAS NSCLC cells, FAK inhibition resulted in persistent DNA damage and susceptibility to exposure to IR. Accordingly, administration of IR to FAK-null tumor xenografts causes a profound antitumor effect in vivo. Conclusions: FAK is a novel regulator of DNA damage repair in mutant KRAS NSCLC and its pharmacologic inhibition leads to radiosensitizing effects that could be beneficial in cancer therapy. Our results provide a framework for the rationale clinical testing of FAK inhibitors in NSCLC patients. (C) 2016 AACR.
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