Université de Nantes, CHU Nantes, CNRS, INSERM, Institut du Thorax, Nantes, France.
SATT Ouest Valorisation, 30 boulevard Vincent Gâche, CS 70211, 44202 Nantes Cedex, France.
Pharmacol Res. 2022 May;179:106220. doi: 10.1016/j.phrs.2022.106220. Epub 2022 Apr 9.
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.
尽管有新的靶向和免疫疗法，但肝细胞癌 (HCC) 患者的预后仍然黯淡，尤其是对于晚期和/或转移性形式。药物耐药性的迅速出现是 HCC 化疗、靶向、免疫治疗成功的主要障碍。需要新的靶点。小 GTPase Rac1 在 HCC 的发展和进展中的突出作用，以及其与多种蛋白质伙伴的相互作用，以及用基于 RNA 的调节剂和小分子靶向 Rac1，在这里进行了讨论。我们讨论了 Rac1 在 HCC 中的致癌功能，包括 Rac1 突变体和同工型 Rac1b 的贡献。Rac1 是一种普遍的靶点，但在 HCC 中经常过度表达和过度激活。它有助于疾病的侵袭性，在癌细胞增殖、肿瘤转移和对治疗的耐药性方面发挥关键作用。直接或间接靶向 Rac1 的小分子已在 HCC 实验模型中显示出抗癌作用。Rac1 结合剂，如 EHT 1864 和类似物，为对抗 HCC 提供了新的机会。我们讨论了用小分子抑制 HCC 中 Rac1 过度激活的不同方式，以及与参考药物联合使用以促进癌细胞死亡和抑制细胞侵袭的方式。我们强调有必要结合 Rac1 靶向方法和适当的生物标志物来选择 Rac1 激活的肿瘤。我们的分析强调了 Rac1 在 HCC 中的突出致癌功能，并讨论了靶向这种小 GTPase 的方式。Rac1 应被视为限制 HCC 肿瘤获得性和固有耐药性及其转移潜力的有效靶点。
