当前位置: X-MOL 学术Mol. Cancer Ther. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Metabolic adaptations to MEK and CDK4/6 co-targeting in uveal melanoma
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2020-05-19 , DOI: 10.1158/1535-7163.mct-19-1016
Jessica L F Teh 1 , Timothy J Purwin 1 , Anna Han 1 , Vivian Chua 1 , Prem Patel 1 , Usman Baqai 1 , Connie Liao 1 , Nelisa Bechtel 1 , Takami Sato 2, 3 , Michael A Davies 4 , Julio Aguirre-Ghiso 5, 6, 7 , Andrew E Aplin 1, 3
Affiliation  

Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK–ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)–positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.

中文翻译:

葡萄膜黑色素瘤对 MEK 和 CDK4/6 共靶向的代谢适应

葡萄膜黑色素瘤中频繁的 GNAQ 和 GNA11 突变会过度激活 MEK-ERK 信号通路,导致细胞周期蛋白依赖性激酶 (CDK) 和细胞周期进程的异常调节。单独使用 MEK 抑制剂 (MEKi) 在葡萄膜黑色素瘤中显示出较差的疗效,这引发了是否可以垂直抑制下游靶标以提供长期益处的问题。CDK4/6 选择性抑制剂经 FDA 批准与 ER 拮抗剂/芳香酶抑制剂联合用于雌激素受体 (ER) 阳性乳腺癌患者。我们确定了 MEKi 加 CDK4/6 抑制剂 (CDK4/6i) 在葡萄膜黑色素瘤中的作用。在体外,palbociclib,一种 CDK4/6i,通过下调细胞周期蛋白来增强 MEKi 的作用。相比之下,单独的体内 CDK4/6 抑制导致细胞停滞,并且在延迟肿瘤生长方面与 MEKi 加 CDK4/6i 治疗一样有效。RNA 测序揭示了 MEKi 抗性肿瘤和 CDK4/6i 耐受性肿瘤中氧化磷酸化 (OxPhos) 途径的上调。此外,MEKi + CDK4/6i 处理后耗氧率增加。IACS-010759 是一种 OxPhos 抑制剂,与 MEKi + CDK4/6i 联合使用可降低葡萄膜黑色素瘤细胞的存活率。这些数据强调了 OxPhos 在葡萄膜黑色素瘤中响应 MEKi + CDK4/6i 治疗的适应性上调,并表明抑制这种代谢状态可能会提高 MEKi 和 CDK4/6i 组合的疗效。MEKi + CDK4/6i 处理后耗氧率增加。IACS-010759 是一种 OxPhos 抑制剂,与 MEKi + CDK4/6i 联合使用可降低葡萄膜黑色素瘤细胞的存活率。这些数据强调了 OxPhos 在葡萄膜黑色素瘤中响应 MEKi + CDK4/6i 治疗的适应性上调,并表明抑制这种代谢状态可能会提高 MEKi 和 CDK4/6i 组合的疗效。MEKi + CDK4/6i 处理后耗氧率增加。IACS-010759 是一种 OxPhos 抑制剂,与 MEKi + CDK4/6i 联合使用可降低葡萄膜黑色素瘤细胞的存活率。这些数据强调了 OxPhos 在葡萄膜黑色素瘤中响应 MEKi + CDK4/6i 治疗的适应性上调,并表明抑制这种代谢状态可能会提高 MEKi 和 CDK4/6i 组合的疗效。
更新日期:2020-05-19
down
wechat
bug