Open AccessRAC 1 inhibition as a therapeutic target for gefitinib‐resistant non‐small‐cell lung cancer
Author(s) -
Kaneto Naoki,
Yokoyama Satoru,
Hayakawa Yoshihiro,
Kato Shinichiro,
Sakurai Hiroaki,
Saiki Ikuo
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12425
Subject(s) - gefitinib , rac1 , epidermal growth factor receptor , cancer research , cell growth , pi3k/akt/mtor pathway , lung cancer , egfr inhibitors , gene silencing , erlotinib , cancer , biology , medicine , signal transduction , microbiology and biotechnology , biochemistry , gene
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 RAC 1 in EGFR ‐mediated progression of NSCLC . We showed the significant role of RAC 1 pathway in the cell migration or lamellipodia formation by using gene silencing of RAC 1 or induction of constitutive active RAC 1 in EGFR ‐mutant NSCLC cells. Importantly, the RAC 1 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 RAC 1 inhibition were mediated through MEK or PI 3 K independent mechanisms. Collectively, these results open up a new opportunity to control the cancer progression by targeting the RAC 1 pathway to overcome the resistance to EGFR ‐ TKI in NSCLC patients.