journal contribution
posted on 2023-03-31, 18:43 authored by 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 <p>Supplementary Table 2. The table shows the IC50 for FAKi PF-562, 271 for the indicated cell lines. Supplementary Table 3. The table shows the Dq, Do and Dose enhancement ratios of NSCLC cells treated as indicated. Dose enhancement ratios at LD50 and LD20 levels were calculated by direct examination of survival curves. Survival parameters (i.e., Dq and Do) were also derived from survival curves shown in Fig. 4 using the relationship, loge n = Dq/Do.</p>
Funding
CDMRP LCRP
American Cancer Society Scholar
UT Southwestern Friends of the Comprehensive Cancer Center, Texas 4000 (PPS)
Science and Technology Program of Guangzhou, China
NCI
Lung Cancer Moonshot Program
V Foundation Grant
Ford Petrin Donation
CCSG Program
The University of Texas Southwestern Medical Center and The University of Texas MD Anderson Cancer Center Lung SPORE grant
NIH Cancer Center
History
ARTICLE 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. Clin Cancer Res; 22(23); 5851–63. ©2016 AACR.
