Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition.
Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition.
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DOI：
10.1016/j.neo.2021.11.009
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Pitson SM
中科院分区：
文献类型：
--
作者：
Bennett MK;Li M;Tea MN;Pitman MR;Toubia J;Wang PP;Anderson D;Creek DJ;Orlowski RZ;Gliddon BL;Powell JA;Wallington-Beddoe CT;Pitson SM
将蛋白酶体抑制剂硼替佐米引入骨髓瘤的治疗方案中已导致患者生存率的显著改善。然而，虽然硼替佐米在许多骨髓瘤患者中具有初始应答，但由于获得性硼替佐米耐药性的发展，这种血液恶性肿瘤仍然无法治愈。由于其他患者的疾病本质上是硼替佐米耐药的，很明显，迫切需要新的治疗方法来靶向硼替佐米耐药的骨髓瘤。我们之前已经证明，鞘氨醇激酶2（SK2）抑制剂K145与硼替佐米联合靶向鞘脂代谢可诱导硼替佐米初治骨髓瘤的协同死亡。在目前的研究中，我们已经证明，K145靶向鞘脂代谢与硼替佐米协同作用，并有效地使硼替佐米耐药骨髓瘤对这种蛋白酶体抑制剂重新敏感。值得注意的是，这些作用依赖于未折叠蛋白应答的增强激活，并且在许多单独的骨髓瘤模型中观察到，这些模型似乎具有不同的硼替佐米耐药机制，包括我们描述的具有临床相关蛋白酶体突变的新的硼替佐米耐药骨髓瘤模型。此外，K145还在硼替佐米耐药和卡非佐米耐药骨髓瘤细胞中显示出与下一代蛋白酶体抑制剂卡非佐米的协同作用。总之，这些发现表明，在蛋白酶体抑制剂耐药背景下，通过SK2抑制靶向鞘脂代谢与广谱蛋白酶体抑制剂联合使用可能有效，是一种值得临床探索的方法。
The introduction of the proteasome inhibitor bortezomib into treatment regimens for myeloma has led to substantial improvement in patient survival. However, whilst bortezomib elicits initial responses in many myeloma patients, this haematological malignancy remains incurable due to the development of acquired bortezomib resistance. With other patients presenting with disease that is intrinsically bortezomib resistant, it is clear that new therapeutic approaches are desperately required to target bortezomib-resistant myeloma. We have previously shown that targeting sphingolipid metabolism with the sphingosine kinase 2 (SK2) inhibitor K145 in combination with bortezomib induces synergistic death of bortezomib-naïve myeloma. In the current study, we have demonstrated that targeting sphingolipid metabolism with K145 synergises with bortezomib and effectively resensitises bortezomib-resistant myeloma to this proteasome inhibitor. Notably, these effects were dependent on enhanced activation of the unfolded protein response, and were observed in numerous separate myeloma models that appear to have different mechanisms of bortezomib resistance, including a new bortezomib-resistant myeloma model we describe which possesses a clinically relevant proteasome mutation. Furthermore, K145 also displayed synergy with the next-generation proteasome inhibitor carfilzomib in bortezomib-resistant and carfilzomib-resistant myeloma cells. Together, these findings indicate that targeting sphingolipid metabolism via SK2 inhibition may be effective in combination with a broad spectrum of proteasome inhibitors in the proteasome inhibitor resistant setting, and is an approach worth clinical exploration.
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核因子（红细胞衍生2）样2和蛋白酶体成熟蛋白轴介导多发性骨髓瘤中的硼替佐米耐药性
影响因子：
4.8
作者：
Li, Bingzong;Fu, Jinxiang;Orlowski, Robert Z.
通讯作者：
Orlowski, Robert Z.
影响因子：
4.1
作者：
Boslem, Ebru;MacIntosh, Gemma;Biden, Trevor J.
通讯作者：
Biden, Trevor J.
影响因子：
7.3
作者：
Aurelio, Luigi;Scullino, Carmen V.;Flynn, Bernard L.
通讯作者：
Flynn, Bernard L.
DOI：
10.2217/fon.11.42
发表时间：
2011-05
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Khan ML;Stewart AK
通讯作者：
Stewart AK
影响因子：
64.8
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.