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.

中文翻译：

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基于卡非佐米的新型组合作为脂肪肉瘤的潜在治疗策略。


蛋白酶体抑制剂，如硼替佐米和卡非佐米，已在血液疾病的抗癌治疗中显示出疗效，但在实体癌中却无效。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，例如 selinexor，一种 XPO1 介导的核输出抑制剂。通过定量核蛋白分析和磷酸激酶阵列，我们确定了该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 PRAS40。此外，通过评估整体蛋白质水平变化，发现调节脂肪酸合成的关键酶 FADS2 在蛋白酶体抑制后下调。有趣的是，FADS2 抑制剂 SC26196 与卡非佐米具有协同作用。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）可增强卡非佐米的体外和体内功效。总而言之，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。