Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.
Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.
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DOI：
10.1038/nm.4372
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发表时间：
2017-09
期刊：
影响因子：
82.9
通讯作者：
Theurillat JP
中科院分区：
文献类型：
--
作者：
Janouskova H;El Tekle G;Bellini E;Udeshi ND;Rinaldi A;Ulbricht A;Bernasocchi T;Civenni G;Losa M;Svinkina T;Bielski CM;Kryukov GV;Cascione L;Napoli S;Enchev RI;Mutch DG;Carney ME;Berchuck A;Winterhoff BJN;Broaddus RR;Schraml P;Moch H;Bertoni F;Catapano CV;Peter M;Carr SA;Garraway LA;Wild PJ;Theurillat JP
通常认为给定癌症驱动基因内的反复突变会引起类似的药物反应。癌症基因组研究已在子宫内膜癌和前列腺癌中的泛素连接酶接头 SPOP 的底物识别域中发现了反复出现但不同的错义突变。它们的治疗意义仍不完全清楚。在这里，我们分析了子宫内膜癌相关 SPOP 突变引起的泛素景观变化，并鉴定了 BRD2、BRD3 和 BRD4 蛋白 (BET) 作为 SPOP-CUL3 底物，优先被子宫内膜 SPOP 突变体降解。由此产生的 BET 蛋白水平降低使癌细胞对 BET 抑制剂敏感。相反，前列腺癌特异性 SPOP 突变体会损害 BET 的降解，从而促进对其药理抑制的抵抗。这些结果揭示了一个肿瘤基因组学悖论，即同一域内的突变会引起相反的药物敏感性。具体来说，我们提供了使用 BET 抑制剂治疗具有 SPOP 突变的子宫内膜癌而非前列腺癌患者的分子原理。
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations in the substrate recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancer. Their therapeutic implications remain incompletely understood. Here, we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutants impaired degradation of BETs, promoting resistance against their pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations within the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat endometrial but not prostate cancer patients with SPOP mutations.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
48
作者：
Mertins, Philipp;Qiao, Jana W.;Patel, Jinal;Udeshi, Namrata D.;Clauser, Karl R.;Mani, D. R.;Burgess, Michael W.;Gillette, Michael A.;Jaffe, Jacob D.;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
16
作者：
Gan W;Dai X;Lunardi A;Li Z;Inuzuka H;Liu P;Varmeh S;Zhang J;Cheng L;Sun Y;Asara JM;Beck AH;Huang J;Pandolfi PP;Wei W
通讯作者：
Wei W