Background/Objective: Ovarian clear cell carcinomas (OCCCs) are a rare histological subtype of epithelial ovarian cancer characterized by resistance to platinum-based therapy. CDK8/19, a component of the regulatory CDK module associated with Mediator complex, has been implicated in transcriptional reprogramming and drug resistance in various solid tumors. Our study aimed to investigate the therapeutic potential of CDK8/19 kinase inhibition using selective inhibitors SNX631 and SNX631-6 in OCCC treatment, both as monotherapy and in combination with standard chemotherapeutics. Methods: CDK8 and Ki67 levels were evaluated via immunohistochemistry in benign, primary, and metastatic ovarian cancer tissues. The efficacy of SNX631 alone and in combination with cisplatin or paclitaxel was assessed in OCCC cell lines (ES-2, TOV-21-G, RMG-1). In vivo evaluation utilized xenograft models with subcutaneous and intraperitoneal delivery of the OCCC ES2 cells and oral delivery of SNX631-6, with the monitoring of tumor growth, metastatic spread, and survival. Results: CDK8 protein levels were elevated in OC tissues, particularly in OCCC primary and metastatic lesions compared to benign tissue. While CDK8/19 inhibition showed limited effects on in vitro cell proliferation, SNX631-6 demonstrated significant antitumor and anti-metastatic activity in vivo. Notably, SNX631-6 enhanced the efficacy of cisplatin, substantially inhibiting tumor growth and extending overall survival. Conclusions: Therapeutically achievable doses of CDK8/19 inhibitors may provide clinical benefit for OCCC patients by inhibiting tumor growth and reversing platinum resistance, potentially addressing a critical treatment challenge in this rare ovarian cancer subtype.
背景/目的：卵巢透明细胞癌是上皮性卵巢癌中一种罕见的组织学亚型，其特征是对铂类化疗药物具有耐药性。CDK8/19是与中介体复合物相关的调节性CDK模块的组成部分，已被证实与多种实体瘤的转录重编程和耐药性相关。本研究旨在探讨使用选择性抑制剂SNX631和SNX631-6抑制CDK8/19激酶在卵巢透明细胞癌治疗中的潜力，包括单药治疗以及与标准化疗药物的联合应用。方法：通过免疫组织化学方法评估良性、原发性和转移性卵巢癌组织中CDK8和Ki67的表达水平。在卵巢透明细胞癌细胞系（ES-2、TOV-21-G、RMG-1）中评估了SNX631单药以及与顺铂或紫杉醇联合使用的疗效。体内评估采用异种移植模型，通过皮下和腹腔注射卵巢透明细胞癌ES2细胞，并口服给予SNX631-6，监测肿瘤生长、转移扩散和生存情况。结果：与良性组织相比，卵巢癌组织中CDK8蛋白水平升高，尤其在卵巢透明细胞癌的原发性和转移性病灶中更为明显。尽管CDK8/19抑制在体外对细胞增殖的影响有限，但SNX631-6在体内表现出显著的抗肿瘤和抗转移活性。值得注意的是，SNX631-6增强了顺铂的疗效，显著抑制了肿瘤生长并延长了总生存期。结论：治疗剂量的CDK8/19抑制剂可能通过抑制肿瘤生长和逆转铂类耐药，为卵巢透明细胞癌患者提供临床获益，有望解决这一罕见卵巢癌亚型的关键治疗挑战。
肿瘤(癌症)患者之家