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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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Epidermal growth factor receptor (EGFR) signaling regulates the cell migration of non-small-cell lung cancer cells. PC-9 cells were incubated for 24 h with 10–10,000 nM gefitinib (gef) after with or without scratching. After 24 h incubation, relative growth (open circle) to vehicle control (−) was determined by WST-1 assay and relative wound closure (closed square) was calculated from the scratched width filled after 24 h incubation compared with at 0 h and normalized to vehicle control (−). Data are the means ± SD of at least three independent experiments. *P < 0.01 by one-way anova followed by the Bonferroni post-hoc test compared with vehicle control.
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fig01: Epidermal growth factor receptor (EGFR) signaling regulates the cell migration of non-small-cell lung cancer cells. PC-9 cells were incubated for 24 h with 10–10,000 nM gefitinib (gef) after with or without scratching. After 24 h incubation, relative growth (open circle) to vehicle control (−) was determined by WST-1 assay and relative wound closure (closed square) was calculated from the scratched width filled after 24 h incubation compared with at 0 h and normalized to vehicle control (−). Data are the means ± SD of at least three independent experiments. *P < 0.01 by one-way anova followed by the Bonferroni post-hoc test compared with vehicle control.

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 (ΔE746-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.


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)

Epidermal growth factor receptor (EGFR) signaling regulates the cell migration of non-small-cell lung cancer cells. PC-9 cells were incubated for 24 h with 10–10,000 nM gefitinib (gef) after with or without scratching. After 24 h incubation, relative growth (open circle) to vehicle control (−) was determined by WST-1 assay and relative wound closure (closed square) was calculated from the scratched width filled after 24 h incubation compared with at 0 h and normalized to vehicle control (−). Data are the means ± SD of at least three independent experiments. *P < 0.01 by one-way anova followed by the Bonferroni post-hoc test compared with vehicle control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Epidermal growth factor receptor (EGFR) signaling regulates the cell migration of non-small-cell lung cancer cells. PC-9 cells were incubated for 24 h with 10–10,000 nM gefitinib (gef) after with or without scratching. After 24 h incubation, relative growth (open circle) to vehicle control (−) was determined by WST-1 assay and relative wound closure (closed square) was calculated from the scratched width filled after 24 h incubation compared with at 0 h and normalized to vehicle control (−). Data are the means ± SD of at least three independent experiments. *P < 0.01 by one-way anova followed by the Bonferroni post-hoc test compared with vehicle control.
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 (ΔE746-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.

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