The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

Abstract

The family of Rho GTPases are involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions, including growth, motility, and survival. Rac1, one of the best characterized Rho GTPases, is an established effector of receptors and an important node in signaling networks crucial for tumorigenesis and metastasis. Rac1 hyperactivation is common in human cancer, and could be the consequence of overexpression, abnormal upstream inputs, deregulated degradation, and/or anomalous intracellular localization. More recently, cancer associated gain-of-function mutations in Rac1 have been identified which contribute to tumor phenotypes and confer resistance to targeted therapies. Deregulated expression/activity of Rac Guanine nucleotide Exchange Factors (GEFs) responsible for Rac activation has been largely associated to a metastatic phenotype and drug resistance. Translating our extensive knowledge in Rac pathway biochemistry into a clinical setting still remains a major challenge, nonetheless remarkable opportunities for cancer therapeutics arise from promising lead compounds targeting Rac and its effectors.

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…P-Rex1 is activated by human epidermal growth factor receptor (HER2) and GPCRs, such as the chemokine receptor CXCR4 in breast cancer, and overexpressed in ER and HER2 positive luminal A and B breast cancer tissues compared to normal breast tissue. P-Rex1 expression was actually low in triple-negative primary tumors but was upregulated in distant metastases (Marotti et al, 2017;Casado-Medrano et al, 2018;Kazanietz et al, 2018). Furthermore, demethylation in the PREX promoter has been associated with breast cancer mortality (Montero et al, 2011).…”

“…The pivotal role of Rac and Cdc42 in multiple cancers has been extensively reviewed by us and others (Pai et al, 2010;Mack et al, 2011;Stengel and Zheng, 2011;Wertheimer et al, 2012;Bid et al, 2013;Kazanietz and Caloca, 2017;Casado-Medrano et al, 2018;Maldonado and Dharmawardhane, 2018;De et al, 2019). In addition, the related Rho GTPase Rho has also been implicated in tumorigenesis and cancer progression.…”

P-REX1-Independent, Calcium-Dependent RAC1 Hyperactivation in Prostate Cancer

“…In summary, our work identified Rac1 and Cdc42 hyperactivation in aggressive androgen-insensitive DU145 and PC3 prostate cancer cell lines. These proteins and their regulators are known to play important roles in the progression of cancer and are therefore of interest as potential therapeutic targets [3]. We have also demonstrated that targeting P-Rex1, a previously identified therapeutic target candidate, is unlikely to have an impact on Rac1 activation status, migration or invasion in prostate cancer cells.…”

“…One is that multiple GEFs are required for maintaining Rac1-GTP and Cdc42-GTP in these cells, and thus silencing single GEFs is insufficient to cause an effect. We cannot rule out that a Rac-GEF not included in our screen could be involved, albeit a less likely possibility because our analysis encompasses the majority of known Rac-GEFs [3]. However, it is quite remarkable that no Dbl or DOCK family GEFs were identified in our proteomics analysis using a nucleotide free Rac1 bait, which is designed to pull-down Rac1 associated GEFs.…”

“…The small GTPases Rac1 and Cdc42 have been recognized as major players in cancer progression and perform essential roles in metastasis [3][4][5]. These G-proteins are members of the Rho-GTPase family, and as such they are binary switches that cycle between an active GTP-bound state and an inactive GDP-bound state.…”