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Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maria Del Mar Maldonado1, Julia Isabel Medina1, Luis Velazquez1

  • 1Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.

Frontiers in Cell and Developmental Biology
|April 24, 2020
PubMed

Insights

Rac and Cdc42 GTPases drive cancer metastasis and therapy resistance. Inhibiting their guanine nucleotide exchange factors (GEFs) offers a promising targeted therapy strategy for metastatic cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Rho family GTPases, including Rac and Cdc42, are crucial regulators of cell division and actin cytoskeleton dynamics.
  • These GTPases play essential roles in cell growth, migration, invasion, polarity, and adhesion, making them key players in cancer metastasis.
  • Dysregulation of Rac and Cdc42 is frequently observed in various cancer types, contributing to disease progression and therapeutic challenges.

Purpose of the Study:

  • To review the role of Rac and Cdc42 GTPases in driving cancer metastasis and therapy resistance.
  • To highlight the involvement of guanine nucleotide exchange factors (GEFs) from the Dbl and DOCK families in Rac/Cdc42 hyperactivation in cancer.
  • To discuss recent advancements in developing inhibitors targeting Rac/Cdc42 GEFs for metastatic cancer therapy.

Main Methods:

  • Literature review focusing on Rac and Cdc42 GTPases and their associated GEFs in cancer.
  • Analysis of signaling pathways involving oncogenic cell surface receptors that activate Rac/Cdc42 GEFs.
  • Examination of preclinical and clinical developments in Rac/Cdc42 GEF-targeting inhibitors.

Main Results:

  • Rac and Cdc42 are frequently hyperactivated in cancer by GEFs, often downstream of oncogenic receptors.
  • Numerous Rac/Cdc42 GEFs are implicated in promoting cancer cell migration, invasion, and resistance to therapy.
  • Targeting Rac/Cdc42 GEF-mediated activation presents a viable therapeutic strategy.

Conclusions:

  • Rac and Cdc42 GTPases are critical mediators of cancer metastasis and therapy resistance.
  • Inhibiting oncogenic Rac/Cdc42 GEFs represents a promising targeted therapy approach for metastatic cancers.
  • Development of Rac and Cdc42 GEF inhibitors holds potential for overcoming treatment resistance and improving patient outcomes.
Keywords:
Cdc42Racguanine nucleotide exchange factor (GEF)guanine nucleotide exchange factorsmetastasismetastasis therapytargeted (selective) treatment

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