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

Authors

  • Naoki Kaneto,

    1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
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  • Satoru Yokoyama,

    Corresponding author
    1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
    • Correspondence Satoru Yokoyama, Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

      Tel: +81-76-434-7621; Fax: +81-76-434-5058;

      E-mail: yokoyama@inm.u-toyama.ac.jp

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  • Yoshihiro Hayakawa,

    1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
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  • Shinichiro Kato,

    1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
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  • Hiroaki Sakurai,

    1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
    2. Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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  • Ikuo Saiki

    1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
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  • Funding Information Grant-in-aid for Challenging Exploratory Research 24659348. Grant-in-aid 24700971 for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. NOVARTIS Foundation (Japan) for the Promotion of Science. Grant-in-aid for JSPS Fellows (DC2) 2510159 from Japan Society for the Promotion of Science.

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.

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