Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona.
Department of Urology, University of Arizona, Tucson, Arizona.
Cancer Res Commun. 2023 Feb 13;3(2):245-257. doi: 10.1158/2767-9764.CRC-22-0340. eCollection 2023 Feb.
Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%-40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism.
Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.
尽管顺铂仍然是多种恶性肿瘤标准治疗化疗方案的骨干，但它的使用常与严重的剂量限制毒性（DLT）相关。值得注意的是，用顺铂为基础的方案治疗的 30%-40%的患者由于 DLT 而发生肾毒性，被迫停止治疗。同时预防肾毒性而又提高治疗反应的新方法有可能对多种癌症患者产生重大的临床影响。在这里，我们报告pevonedistat（MLN4924），一种首创的 NEDDylation 抑制剂，可缓解肾毒性并在头颈部鳞状细胞癌（HNSCC）模型中协同增强顺铂的疗效。我们证明 pevonedistat 通过硫氧还蛋白相互作用蛋白（TXNIP）介导的机制保护正常肾细胞免受损伤，同时增强顺铂的抗癌活性。pevonedistat 和 cisplatin 的联合治疗在 100%的治疗小鼠中产生了显著的 HNSCC 肿瘤消退和长期动物生存。重要的是，联合治疗减少了 cisplatin 单药治疗引起的肾毒性，表现为阻断肾损伤分子-1（KIM-1）和 TXNIP 的表达，减少塌陷的肾小球和坏死的铸型形成，以及抑制 cisplatin 介导的动物体重减轻。NEDDylation 的抑制代表了一种预防顺铂诱导的肾毒性的新策略，同时通过氧化还原介导的机制增强其抗癌活性。
顺铂治疗与显著的肾毒性相关，限制了其临床应用。在这里，我们证明 pevonedistat 的 NEDDylation 抑制是一种选择性预防顺铂诱导的肾脏氧化损伤的新方法，同时增强其抗癌疗效。需要对 pevonedistat 和 cisplatin 的联合治疗进行临床评估。
