Approaches of targeting Rho GTPases in cancer drug discovery

Expert Opin Drug Discov. 2015;10(9):991-1010. doi: 10.1517/17460441.2015.1058775. Epub 2015 Jun 18.


Introduction: Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression, and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed "undruggable" because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells.

Areas covered: This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, that is, RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases, and posttranslational modifications at a molecular level.

Expert opinion: To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small-molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents.

Keywords: Cdc42; Rac1; Rho GTPases; RhoA; RhoGEF; cancer; small molecule inhibitor; targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Drug Design
  • Drug Discovery / methods
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Signal Transduction / drug effects
  • rho GTP-Binding Proteins / antagonists & inhibitors*
  • rho GTP-Binding Proteins / metabolism


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • rho GTP-Binding Proteins