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: To understand the role of EGFR signaling in other than NSCLC cell growth or survival, we firstly investigated the effects of EGFR signaling on cell migration by using an in vitro wound healing assay. In human NSCLC cell line PC-9 expressing mutant EGFR (Î”E746-A750), which has constitutively activated EGFR signaling without extrinsic ligand stimulation,(30) we found that the migratory ability was clearly impaired after gefitinib treatment at 300 nM for 24 h; that in the condition cell growth was not affected (Figs 1a,S1). Given that the migration of the A549 cell line expressing wild-type EGFR was increased after recombinant EGF stimulation (data not shown), both cell intrinsic and extrinsic EGFR signaling regulated the cell migration of NSCLC cells in addition to regulating their cell growth and survival.
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.