Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer

Ke Jing Tang, Jerfiz D. Constanzo, Niranjan Venkateswaran, Margherita Melegari, Mariya Ilcheva, Julio C. Morales, Ferdinandos Skoulidis, John V. Heymach, David A. Boothman, Pier Paolo Scaglioni

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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. Clin Cancer Res; 22(23); 5851-63.

Original languageEnglish (US)
Pages (from-to)5851-5863
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tang, K. J., Constanzo, J. D., Venkateswaran, N., Melegari, M., Ilcheva, M., Morales, J. C., Skoulidis, F., Heymach, J. V., Boothman, D. A., & Scaglioni, P. P. (2016). Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer. Clinical Cancer Research, 22(23), 5851-5863. https://doi.org/10.1158/1078-0432.CCR-15-2603