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 identify the downstream molecular mechanism that regulates the migration of PC-9 cells under EGFR activation, we next examined the chemical inhibition of various signaling pathways in PC-9 cell migration. Among four compounds tested that are known to inhibit EGFR-related signaling pathways (PI3K, MEK, p38 and RAC1), only RAC1 inhibitor (NSC23766) suppressed PC-9 cell migration at a similar level to gefitinib (Fig. 2a). Considering that RAC1 is a member of the Rho family of small GTPase, we next examined the effect of gefitinib on the expression level of RAC1-GTP, which is an active form of RAC1, in PC-9 cells. Interestingly, we observed both the reduction of RAC1-GTP and the induction of RAC1 Ser71 phosphorylation in PC-9 cells after gefitinib treatment besides the reduced phosphorylation of molecules associated with cell growth and survival, such as p38, Akt and ERK1/2 (Fig. 2b). In addition to such inactivation of RAC1 molecules, the formation of lamellipodia, known as an important cellular function of RAC1, was diminished after gefitinib treatment in PC-9 cells (Fig. 2c). We further directly confirmed the essential role of RAC1 in NSCLC cell migration by knocking down RAC1 protein using siRNA against RAC1 (Fig. 2d). Given that the phosphorylation of p38, Akt and ERK1/2 was not affected by knocking down RAC1 in PC-9 cells, RAC1 likely regulates the cell migration of PC-9 cells apart from the conventional downstream cell survival pathway of EGFR signaling.
Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.