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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) 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.​ 

Author information​

Tang KJ1,2,3, Constanzo JD2,3, Venkateswaran N2,3, Melegari M3, Ilcheva M3,4, Morales JC3,4, Skoulidis F5, Heymach JV5, Boothman DA3,4, Scaglioni PP6,3.

1Department of Pulmonary Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

2Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

3Simmons Comprehensive Cancer Center and.

4Departments of Radiation Oncology and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.

5Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

6Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Pier.Scaglioni@UTSouthwestern.edu.