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 further determine whether RAC1 suppression is involved in the suppression of cell migration upon gefitinib treatment, we generated PC-9 cells overexpressing constitutive active forms of RAC1, RAC1G12V or RAC1Q61L.(24) As shown in Figure 3(a), the reduced cell migration of PC-9 cells by gefitinib treatment was diminished in RAC1G12V or RAC1Q61L overexpressing PC-9 cells. Furthermore, the reduction of lamellipodia formation (Fig. 3b) by gefitinib treatment was also diminished in both RAC1G12V and RAC1Q61L overexpressing cells. RAC1 overexpression was confirmed by detection of HA tag (Fig. 3c). Collectively, these results strongly support that RAC1 activity is critically involved in EGFR-mediated cell migration of PC-9 cells.
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.