Overexpressed or hyperactivated Rac1 as a target to treat hepatocellular carcinoma

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.

Automated summary

Despite advancements in targeted and immunotherapies, hepatocellular carcinoma (HCC) patients still face poor prognosis, especially in advanced and metastatic forms. Drug resistance, particularly in chemo-, targeted- and immuno-therapies, poses a significant challenge in the treatment of HCC. This article discusses the crucial role of the small GTPase Rac1 in HCC development and progression, along with its protein partners, and explores the potential of RNA-based regulators and small molecules to target Rac1. The oncogenic functions of Rac1 in HCC are highlighted, emphasizing its contribution to aggressive disease behavior such as cancer cell proliferation, tumor metastasis, and treatment resistance. Small molecule targeting of Rac1 has shown anticancer effects in experimental models of HCC. Rac1-binding agents like EHT 1864 and analogues offer new possibilities in combating HCC. The article addresses different approaches to inhibit Rac1 overactivation in HCC using small molecules, in combination with reference drugs, to induce cancer cell death and suppress cell invasion. It emphasizes the need to combine Rac1-targeted therapy with appropriate biomarkers for the selection of Rac1-activated tumors. The analysis underscores Rac1 as a potential target to overcome acquired and intrinsic resistance in HCC tumors and their metastatic potential.