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Review
. 2020 Apr 8:8:201.
doi: 10.3389/fcell.2020.00201. eCollection 2020.

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maria Del Mar Maldonado  1 , Julia Isabel Medina  1 , Luis Velazquez  1 , Suranganie Dharmawardhane  1
Affiliations
Review

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maria Del Mar Maldonado et al. Front Cell Dev Biol. .

Abstract

The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

Keywords: Cdc42; Rac; guanine nucleotide exchange factor (GEF); guanine nucleotide exchange factors; metastasis; metastasis therapy; targeted (selective) treatment.

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Figures

FIGURE 1
FIGURE 1
Receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) and Integrin pathways converge in the activation of Rac and Cdc42 GEFs. Cell surface receptors activate GEFs by a variety of mechanisms, involving phosphoinside 3-kinase (PI3-K)-mediated production of phosphatidyl-inositol (3,4,5) tris phosphate (PIP3), which activates GEFs such as P-Rex1, DOCKs, and Vavs; Ras, which activates Tiam-1; and Focal adhesion kinase (FAK)/ signaling to activate ELMO a partner for DOCK1. Upregulation of Rac and Cdc42 can lead to resistance to cell surface receptor targeted therapies (eg. Trastuzumab, Lapatinib, Gefitinib, Eroltinib). Rac/Cdc42-interaction inhibitors are shown in blue boxes. Color-coding of GEFs represent Rac-exclusive GEFs, Cdc42-exclusive GEFs, and GEFs that interact with both Rac and Cdc42.
See this image and copyright information in PMC

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