Recurrent mutations in SPOP-encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP-mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP, and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic.

中文翻译：

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前列腺癌相关的SPOP突变通过BRD4的稳定赋予对BET抑制剂的耐药性

前列腺癌中编码基于Cullin 3的E3泛素连接酶的SPOP中的反复突变破坏了包括BET蛋白在内的泛素化底物的识别和降解。因此，增强了BET蛋白的稳定性，这增加了对SPOP突变型前列腺肿瘤中BET抑制剂的抵抗力。这些结果以及Janouskova等人的结果。和Zhang等人，揭示了一种新的抗BET抑制的非遗传机制，该机制涉及SPOP中癌症类型特异性突变，并支持对SPOP突变的评估，从而为临床上的BET抑制剂管理提供依据。