<scp>RAC</scp>1 inhibition as a therapeutic target for gefitinib‐resistant non‐small‐cell lung cancer

Kaneto, Naoki; Yokoyama, Satoru; Hayakawa, Yoshihiro; Kato, Shinichiro; Sakurai, Hiroaki; Saiki, Ikuo

doi:10.1111/cas.12425

Cited by 44 publications

(43 citation statements)

References 35 publications

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“…Rac1 promoted colon cancer progression through promotion of cell proliferation, survival and migration (36). Rac1 expression is correlated with tumorigenesis, aggressiveness and treatment resistance in a number of cancers such as lung (37,38), breast cancer (39,40) and melanoma (23,41). These clinical investigations have shown the close correlation of Rac1 with human cancers.…”

Section: Discussionmentioning

confidence: 99%

“…They further found that inhibition of Rac1 activity could be useful in overcoming treatment resistance and could be proposed for hNSCC patients with primary or secondary chemoradioresistance (43). In addition, Kaneto et al (38) discovered that Rac1 inhibition was a potential therapeutic target for gefitinib-resistant non-small cell lung cancer (NSCLC). In agreement with the study of Kaneto et al, another group found that Rac1 suppression could suppress NSCLC stem cells and thus inhibit their tumorigenic activity (44).…”

Section: Discussionmentioning

confidence: 99%

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Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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Abstract. Rac1 is a member of the Rho GTPase family. Rac1 activity is critical in regulating cytoskeleton organization and thus, modulates a diverse spectrum of cellular functions in normal and malignant cells. The aims of the present study were to investigate the expression pattern and clinical significance of Rac1, as well as the role of Rac1 in gastric cancer tumorigenesis and metastasis. The expression of Rac1 in human gastric cancer was explored by immunohistochemistry. The correlation of Rac1 expression with the clinicopathological characteristics and the survival of patients were analyzed by Pearson's Chi-square and KaplanMeier analyses, respectively. Rac1 overexpression cell model was used to examine in vitro and in vivo effects of Rac1 in cell growth, migration and invasion. Rac1 was highly expressed in gastric cancer tissues and correlated with differentiation, local invasion, lymph node metastasis and Lauren's classification. Rac1 expression in gastric cancer predicted shorter survival. Overexpression of Rac1 in gastric cancer cells dramatically induced Rac1 activation and rendered a more aggressive phenotype such as increased cell growth and migration/invasion in vitro and in vivo. Inhibiting Rac1 activity by specific inhibitor abrogated the effects of Rac1 on the malignant phenotype. Our clinical findings demonstrated that Rac1 was well correlated with aggressiveness and a negative prognostic factor. In addition, our data on experimental cell models supported the fundamental role of Rac1 in gastric cancer. Given its pivotal role in gastric tumorigenesis and progression, Rac1 can serve as a promising therapeutic target for gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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“…Despite this,i ti sa dvertised as as pecific inhibitor and has been used to identify Rac1 as anew therapeutic target for the influenza virus,a nd in gefitinib-resistant non-small cell lung cancer. [126] It has also been reported that NSC23766 acts as ac ompetitive antagonist at muscarinic acetylcholine [127] and NMDA [128] receptors in aR ac1-independent manner,a tt he same concentrations used for Rac1 inhibition. Moreover,i t had critical, Rac1-independent, off-target effects in platelets [129] resulting in the authors concluding the lack of specificity limits their potential without further analysis.…”

Section: Discussionmentioning

confidence: 95%

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

2020

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The Ras superfamily of small GTPases are guanine‐nucleotide‐dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP‐dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re‐evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell‐based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.

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“…Downregulation of RAC1 can reduce cell activation, such as migration, invasion, and the formation of lamellipodia . Moreover, the inhibition of RAC1 can also sensitize gefitinib‐resistant NSCLC cells to gefitinib . Finally, we speculate that the dysregulation of RAC1 can lead to massive cellular disorders, including platelet function, cell migration, adhesion, intracellular transport, and cellular transformation.…”

Section: Alternative Treatments Against Lung Cancer In Clinical Therapymentioning

confidence: 86%

Emerging roles of RAC1 in treating lung cancer patients

et al. 2016

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The Ras-related C3 botulinum toxin substrate 1 (RAC1), a member of the Rho family of small guanosine triphosphatases, is critical for many cellular activities, such as phagocytosis, adhesion, migration, motility, cell proliferation, and axonal growth. In addition, RAC1 plays an important role in cancer angiogenesis, invasion, and migration, and it has been reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Recently, the therapeutic target of RAC1 in cancer has been investigated. In addition, some investigations have shown that inhibition of RAC1 can reverse drug-resistance in non-small cell lung cancer. In this review, we summarize the recent advances in understanding the role of RAC1 in lung cancer and the underlying mechanisms and discuss its value in clinical therapy.

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

Cited by 44 publications

References 35 publications

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

Emerging roles of RAC1 in treating lung cancer patients

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