Approaches of targeting Rho GTPases in cancer drug discovery

Abstract

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, i.e. 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.

RETRACTED: Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma

“…When expression of seven Rho GTPase family members were examined in 53 GA patient tumors and 7 GA cell lines, only Rac1 and RhoA were found to be consistently increased (15). The Rho GTPase family of proteins regulates a diverse array of cellular processes including cell proliferation, metabolism, cytoskeletal reorganization, and activation of protein kinases (16). Rac1 appears to be deregulated in a variety of tumor types, and Rac1 hyperactivation and overexpression seems to correlate well with aggressive growth and other malignant characteristics (17).…”

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

“…(48) Our data implicate that targeting NFIB alone may also be of high yield. Rho signaling has already been the subject of research as a target of precision anticancer therapy given its role in many human cancers,(49), and axonal guidance signaling has also been proposed as a viable therapeutic target. (50) These pathways may be worth investigation in the context of ACC.…”

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

“…[52][53][54] RAC1 small molecule inhibitors are in ongoing development. 55,56 Taken together, these data suggest RAC1 inhibition is a potential therapeutic strategy for PTCLs with VAV1 fusions, noting, however, that these fusions are present in the minority of PTCLs.…”