title: RAC1 inhibition as a therapeutic target for gefitinib-resistant non-small-cell lung cancer.
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.
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kaneto
authors.forename: Satoru
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kato
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; C487513:NSC 23766; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C107953:RAC1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D020830:rac1 GTP-Binding Protein; D000077156:Gefitinib
keywords: Epidermal growth factor receptor tyrosine kinase inhibitors; RAC1; gefitinib; migration; non-small-cell lung cancer
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