title: Focal Adhesion Kinase Regulates the DNA Damage Response and Its Inhibition Radiosensitizes Mutant KRAS Lung Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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. Clin Cancer Res; 22(23); 5851-63. ©2016 AACR.
authors.affiliation: Department of Pulmonary Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.|Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.|Simmons Comprehensive Cancer Center and.
authors.forename: Ke-Jing
authors.initials: KJ
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.|Simmons Comprehensive Cancer Center and.
authors.forename: Jerfiz D
authors.initials: JD
authors.lastname: Constanzo
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.|Simmons Comprehensive Cancer Center and.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Venkateswaran
authors.affiliation: Simmons Comprehensive Cancer Center and.
authors.forename: Margherita
authors.initials: M
authors.lastname: Melegari
authors.affiliation: Simmons Comprehensive Cancer Center and.|Departments of Radiation Oncology and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Mariya
authors.initials: M
authors.lastname: Ilcheva
authors.affiliation: Simmons Comprehensive Cancer Center and.|Departments of Radiation Oncology and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morales
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ferdinandos
authors.initials: F
authors.lastname: Skoulidis
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Simmons Comprehensive Cancer Center and.|Departments of Radiation Oncology and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Pier.Scaglioni@UTSouthwestern.edu.|Simmons Comprehensive Cancer Center and.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034622:RNA Interference / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)