TY - JOUR
T1 - Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer
AU - Tang, Ke Jing
AU - Constanzo, Jerfiz D.
AU - Venkateswaran, Niranjan
AU - Melegari, Margherita
AU - Ilcheva, Mariya
AU - Morales, Julio C.
AU - Skoulidis, Ferdinandos
AU - Heymach, John V.
AU - Boothman, David A.
AU - Scaglioni, Pier Paolo
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85006314283&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006314283&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-2603
DO - 10.1158/1078-0432.CCR-15-2603
M3 - Article
C2 - 27220963
AN - SCOPUS:85006314283
SN - 1078-0432
VL - 22
SP - 5851
EP - 5863
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -