Mutations in SPOP, the gene encoding a component of the E3 ubiquitin ligase complex, impair ubiquitination-dependent degradation of BRD2, BRD3 and BRD4 proteins and result in activation of ATK–mTORC1 signaling and resistance to BET inhibitors. Pharmacological blockade of AKT represents a viable strategy to restore the sensitivity of SPOP-mutant prostate tumors to BET inhibitors. These results, together with findings by Dai et al. and Janouskova et al., uncover a new nongenetic mechanism of resistance to BET inhibition involving cancer-type-specific mutations in SPOP, and support the evaluation of SPOP mutation status to inform the administration of BET inhibitors in the clinic.

中文翻译：

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BET蛋白质稳定化和AKT–mTORC1激活介导SPOP突变型前列腺癌的内在BET抑制剂耐药性

SPOP（一种编码E3泛素连接酶复合物的成分的基因）的突变会削弱BRD2，BRD3和BRD4蛋白的泛素化依赖性降解，并导致ATK-mTORC1信号的激活和对BET抑制剂的抗性。AKT的药理学阻断代表了一种恢复SPOP突变型前列腺肿瘤对BET抑制剂敏感性的可行策略。这些结果以及Dai等人的发现。和Janouskova等人，发现了一种新的抗BET抑制的非遗传机制，该机制涉及SPOP中的癌症类型特异性突变，并支持对SPOP突变状态的评估，以告知临床上BET抑制剂的使用。