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Cited by 122Protein Kinase Regulation and GTPase SignalingMechanisms of cancer metastasisCancer Cells and Metastasis

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

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Maldonado, Maria del Mar, Medina, Julia Isabel, Velazquez, Luis, Dharmawardhane, Suranganie·2020·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2020.00201PMC PMC7156542
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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.

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  • Overactivation of RHO subfamily GTPases such as RAC1 and CDC42 promotes hyperactivation of critical signaling cascades leading to cancer.

    “However, overactivation of the RHO subfamily such as RAS-related C3 botulinum toxin substrate 1 (RAC1) and cell division cycle 42 homolog (CDC42) are also known to promote the hyperactivation of critical signaling cascades leading to cancer (10, 13, 17).”

    From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [17]

    The Introduction describes Rac and Cdc42 as drivers of cancer progression and metastasis and says they activate downstream signaling cascades. The Targeting Rac and Cdc42/GEF Interaction section says Rac1 and Cdc42 can be hyperactivated in cancer. The copy does not establish that their overactivation hyperactivates those cascades or leads to the initial development of cancer, rather than promoting progression. (LLM, conf=0.81)

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Cited by

Sorted by citations

Authors
Maldonado, M. D. M., Medina, J. I., Velazquez, L., & Dharmawardhane, S.
Affiliations
University of Puerto Rico, Medical Sciences Campus (PR)
Corresponding author
Dharmawardhane, Suranganie
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2020-04-08
Volume
8
Pages
201-201
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2020.00201
PMC
PMC7156542
OpenAlex
W3016130545
Cited by
122
References
2
Citations by year
2026: 15 · 2025: 18 · 2024: 23 · 2023: 18 · 2022: 18 · 2021: 25 · 2020: 5
FWCI
1.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • U.S. Department of Defense
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
Rac, Cdc42, guanine nucleotide exchange factor, Rho GTPases, metastasis, targeted cancer therapy, treatment resistance, cell migration and invasion, actin cytoskeleton, integrins, G protein-coupled receptors, growth factor receptors

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