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

Kaneto N, Yokoyama S, Hayakawa Y, Kato S, Sakurai H, Saiki I - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.

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RAC1 inhibitor suppressed gefitinib-resistant non-small-cell lung cancer (NSCLC) tumor growth in vivo. (a) RPC-9 cells were subcutaneously inoculated into mice. Mice received NSC23766 in 20% DMSO (2.5 mg/kg/day) (closed square) or vehicle (open circle) by intraperitoneal administration every day. Tumor volume was measured at the indicated times. Data represented as the mean ± SD (n = 3). *P < 0.01 by two-way anova followed by the Bonferroni post-hoc test. (b) At day 20 after inoculation, tumors were excised and tumor weight was weighed. Data represented as the mean ± SD (n = 3). #P < 0.05 by Student's t-test.
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fig05: RAC1 inhibitor suppressed gefitinib-resistant non-small-cell lung cancer (NSCLC) tumor growth in vivo. (a) RPC-9 cells were subcutaneously inoculated into mice. Mice received NSC23766 in 20% DMSO (2.5 mg/kg/day) (closed square) or vehicle (open circle) by intraperitoneal administration every day. Tumor volume was measured at the indicated times. Data represented as the mean ± SD (n = 3). *P < 0.01 by two-way anova followed by the Bonferroni post-hoc test. (b) At day 20 after inoculation, tumors were excised and tumor weight was weighed. Data represented as the mean ± SD (n = 3). #P < 0.05 by Student's t-test.

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.


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

Kaneto N, Yokoyama S, Hayakawa Y, Kato S, Sakurai H, Saiki I - Cancer Sci. (2014)

RAC1 inhibitor suppressed gefitinib-resistant non-small-cell lung cancer (NSCLC) tumor growth in vivo. (a) RPC-9 cells were subcutaneously inoculated into mice. Mice received NSC23766 in 20% DMSO (2.5 mg/kg/day) (closed square) or vehicle (open circle) by intraperitoneal administration every day. Tumor volume was measured at the indicated times. Data represented as the mean ± SD (n = 3). *P < 0.01 by two-way anova followed by the Bonferroni post-hoc test. (b) At day 20 after inoculation, tumors were excised and tumor weight was weighed. Data represented as the mean ± SD (n = 3). #P < 0.05 by Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317907&req=5

fig05: RAC1 inhibitor suppressed gefitinib-resistant non-small-cell lung cancer (NSCLC) tumor growth in vivo. (a) RPC-9 cells were subcutaneously inoculated into mice. Mice received NSC23766 in 20% DMSO (2.5 mg/kg/day) (closed square) or vehicle (open circle) by intraperitoneal administration every day. Tumor volume was measured at the indicated times. Data represented as the mean ± SD (n = 3). *P < 0.01 by two-way anova followed by the Bonferroni post-hoc test. (b) At day 20 after inoculation, tumors were excised and tumor weight was weighed. Data represented as the mean ± SD (n = 3). #P < 0.05 by Student's t-test.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.

Show MeSH
Related in: MedlinePlus