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 affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations 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 cancer–associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer–specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

中文翻译：

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癌症类型特异性SPOP突变体对BET蛋白降解和对BET抑制剂敏感性的相反作用

通常认为，给定的癌症驱动基因内的反复突变会引起相似的药物反应。癌症基因组研究已经确定了复发但发散的错义突变，这些突变影响子宫内膜癌和前列腺癌中泛素连接酶衔接子SPOP的底物识别域。这些突变的治疗意义尚不完全清楚。在这里，我们分析了由子宫内膜癌相关的SPOP突变引起的遍在蛋白景观的变化，并将BRD2，BRD3和BRD4蛋白（BET）确定为SPOP–CUL3底物，这些底物优先被子宫内膜癌相关的SPOP突变体降解。BET蛋白水平的降低导致癌细胞对BET抑制剂敏感。相反，前列腺癌特异性SPOP突变导致BET的降解受损，从而增强了其对药理抑制的抵抗力。这些结果揭示了肿瘤基因组学悖论，从而映射到相同域的突变引起了相反的药物敏感性。具体而言，我们提供了使用BET抑制剂治疗具有SPOP突变的子宫内膜而非前列腺癌患者的分子原理。