Overexpressed or hyperactivated Rac1 as a target to treat hepatocellular carcinoma

Abstract

Despite novel targeted and immunotherapies, the prognosis remains bleak for patients with hepatocellular carcinoma (HCC), especially for advanced and/or metastatic forms. The rapid emergence of drug resistance is a major obstacle in the success of chemo-, targeted-, immuno-therapies of HCC. Novel targets are needed. The prominent roles of the small GTPase Rac1 in the development and progression of HCC are discussed here, together with its multiple protein partners, and the targeting of Rac1 with RNA-based regulators and small molecules. We discuss the oncogenic functions of Rac1 in HCC, including the contribution of Rac1 mutants and isoform Rac1b. Rac1 is a ubiquitous target, but the protein is frequently overexpressed and hyperactivated in HCC. It contributes to the aggressivity of the disease, with key roles in cancer cell proliferation, tumor metastasis and resistance to treatment. Small molecule targeting Rac1, indirectly or directly, have shown anticancer effects in HCC experimental models. Rac1-binding agents such as EHT 1864 and analogues offer novel opportunities to combat HCC. We discuss the different modalities to repress Rac1 overactivation in HCC with small molecules and the combination with reference drugs to promote cancer cell death and to repress cell invasion. We highlight the necessity to combine Rac1-targeted approach with appropriate biomarkers to select Rac1 activated tumors. Our analysis underlines the prominent oncogenic functions of Rac1 in HCC and discuss the modalities to target this small GTPase. Rac1 shall be considered as a valid target to limit the acquired and intrinsic resistance of HCC tumors and their metastatic potential.

Keywords: (R)-ketorolac (PubChem CID: 181818); 1A-116 (PubChem CID: 71543346); Cancer; Chemo-resistance; EHT 1864 (PubChem CID: 9938202); EHop-016 (PubChem CID: 51031035); GTPase; Hepatocellular carcinoma; MBQ-167 (PubChem CID: 129896932); NSC23766 (PubChem CID: 409805); PTK787 (PubChem CID: 151194); Rac inhibitors; Rac1 protein; Signaling pathways; honokiol (PubChem CID: 72303).