RAC1 inhibition as a therapeutic target for gefitinib-resistant non-small-cell lung cancer.
Bottom Line: 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 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.
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.Show MeSH
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Mentions: Finally, to investigate whether RAC1 inhibition could suppress tumor growth in vivo, we inoculated a human gefitinib-resistant NSCLC cell line, RPC-9 cells, subcutaneously into mice. Consistent with in vitro data, the RAC1 inhibitor, NSC23766, significantly reduced RPC-9 tumor size and weight compared to vehicle control (Fig. 5) without any loss of the body weight of mice (data not shown). This suggested that NSC23766 could inhibit gefitinib-resistant NSCLC tumor growth without severe side effects.
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.