RAC1 inhibition as a therapeutic target for gefitinib‐resistant non‐small‐cell lung cancer

Cancer Science

Naoki Kaneto¹  Satoru Yokoyama¹  Yoshihiro Hayakawa¹  Shinichiro Kato¹  Hiroaki Sakurai¹ 

[1] Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan

关键词: Epidermal growth factor receptor tyrosine kinase inhibitors;    gefitinib;    migration;    non‐small‐cell lung cancer;    RAC1;   

DOI  :  10.1111/cas.12425

来源: Wiley

【 摘 要 】

Abstract

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKI), including gefitinib, provide a significant clinical benefit in non-small-cell lung cancer (NSCLC) patients, the acquisition of drug resistance has been known to limit the efficacy of EGFR-TKI therapy. In this study, we demonstrated the involvement of EGF-EGFR signaling in NSCLC cell migration and the requirement of RAC1 in EGFR-mediated progression of NSCLC. We showed the significant role of RAC1 pathway in the cell migration or lamellipodia formation by using gene silencing of RAC1 or induction of constitutive active RAC1 in EGFR-mutant NSCLC cells. Importantly, the RAC1 inhibition suppressed EGFR-mutant NSCLC cell migration and growth in vitro, and growth in vivo even in the gefitinib-resistant cells. In addition, these suppressions by RAC1 inhibition were mediated through MEK or PI3K independent mechanisms. Collectively, these results open up a new opportunity to control the cancer progression by targeting the RAC1 pathway to overcome the resistance to EGFR-TKI in NSCLC patients.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.