Targeting Rac and Cdc42 GTPases in Cancer

Abstract

Rac and Cdc42 are small GTPases that have been linked to multiple human cancers and are implicated in epithelial to mesenchymal transition, cell-cycle progression, migration/invasion, tumor growth, angiogenesis, and oncogenic transformation. With the exception of the P29S driver mutation in melanoma, Rac and Cdc42 are not generally mutated in cancer, but are overexpressed (gene amplification and mRNA upregulation) or hyperactivated. Rac and Cdc42 are hyperactivated via signaling through oncogenic cell surface receptors, such as growth factor receptors, which converge on the guanine nucleotide exchange factors that regulate their GDP/GTP exchange. Hence, targeting Rac and Cdc42 represents a promising strategy for precise cancer therapy, as well as for inhibition of bypass signaling that promotes resistance to cell surface receptor-targeted therapies. Therefore, an understanding of the regulatory mechanisms of these pivotal signaling intermediates is key for the development of effective inhibitors. In this review, we focus on the role of Rac and Cdc42 in cancer and summarize the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of Rac- and Cdc42-targeting agents. Cancer Res; 78(12); 3101-11. ©2018 AACR.

Conflict of interest statement

Conflict of interest: M Maldonado has no Conflict of Interest.

S Dharmawardhane is an inventor in US patents US 08884006 B2 and US 9278956 B1 and patent applications US 15/499532, PCT/US2017/029921 for Rac/Cdc42 inhibitors.

©2018 American Association for Cancer Research.

Figures

Figure 1. Targeting Rac and Cdc42

Current available inhibitors target Rac and Cdc42 activation by disrupting GEF interactions, inhibiting nucleotide binding, blocking lipid modifications, and modulating Rho GDIs and proteosomal degradation, as well as by inhibiting downstream effector activity.