Focal Adhesion Kinase Regulates the DNA Damage Response and Its Inhibition Radiosensitizes Mutant KRAS Lung Cancer

• Published in: Clinical cancer research 2016-12, Vol.22 (23), p.5851-5863
• Main Authors: Tang, Ke-Jing, Constanzo, Jerfiz D, Venkateswaran, Niranjan, Melegari, Margherita, Ilcheva, Mariya, Morales, Julio C, Skoulidis, Ferdinandos, Heymach, John V, Boothman, David A, Scaglioni, Pier Paolo
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; DNA Damage - drug effects; DNA Damage - genetics; Female; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mice; Mice, Nude; Mutation - drug effects; Mutation - genetics; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins p21(ras) - genetics; Radiation-Sensitizing Agents - metabolism; RNA Interference - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-15-2603

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. We characterized the effects of suppressing focal adhesion kinase (FAK) by RNA 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. 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. Clin Cancer Res; 22(23); 5851-63. ©2016 AACR.