Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas.
Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas.
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新型卡非佐米为基础的组合作为脂肪肉瘤的潜在治疗策略。
DOI：
10.1007/s00018-020-03620-w
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Jeitany M;Prabhu A;Dakle P;Pathak E;Madan V;Kanojia D;Mukundan V;Jiang YY;Landesman Y;Tam WL;Kappei D;Koeffler HP
蛋白酶体抑制剂，如硼替佐米和卡非佐米，在血液病的抗癌治疗中显示出疗效，但在实体癌中没有。在这里，我们发现脂肪肉瘤（LPS）对蛋白酶体抑制敏感，并确定了与卡非佐米协同作用的药物，如selinexor，一种XPO 1介导的核输出抑制剂。通过定量核蛋白质谱和磷酸激酶阵列，我们确定了这种组合的潜在作用模式，包括干扰核糖体生物合成和抑制促生存激酶PRAS 40。此外，通过评估整体蛋白水平的变化，发现FADS 2，一个调节脂肪酸合成的关键酶，在蛋白酶体抑制后下调。有趣的是，FADS 2抑制剂SC26196与卡非佐米有协同作用。最后，为了确定进一步的组合选择，我们进行了高通量药物筛选，并发现了与卡非佐米的新型药物相互作用。例如，环孢菌素A，一种已知的免疫抑制剂，在体外和体内增强了卡非佐米的功效。总之，这些结果表明，卡非佐米及其组合可以重新用于LPS临床管理。本文的在线版本（10.1007/s 00018 -020-03620-w）包含补充材料，可供授权用户使用。
Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib’s efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management. The online version of this article (10.1007/s00018-020-03620-w) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
28.5
作者：
Kanojia D;Garg M;Martinez J;M T A;Luty SB;Doan NB;Said JW;Forscher C;Tyner JW;Koeffler HP
通讯作者：
Koeffler HP
DOI：
10.1038/nrm.2017.73
发表时间：
2018-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Gomez-Pastor R;Burchfiel ET;Thiele DJ
通讯作者：
Thiele DJ