CULLIN3-based E3 ubiquitin ligase substrate-binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient-derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non-hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti-cancer efficacy of NEO2734 in SPOP-mutated PCa patients.

中文翻译：

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新型BET-CBP / p300双重抑制剂NEO2734在SPOP突变和野生型前列腺癌中具有活性。

基于CULLIN3的E3泛素连接酶底物结合适配子基因SPOP在前列腺癌（PCa）中经常发生突变。携带SPOP热点突变体（例如F133V）的PCa对BET抑制剂具有抗性，因为BET蛋白异常升高。在这里，我们在患者的原发性和转移性PCa中的SPOP MATH域边缘发现了一个先前无法识别的突变Q165P。Q165P突变会导致MATH结构域发生结构变化，并损害SPOP二聚化和底物降解。与F133V热点突变肿瘤不同，Q165P突变患者源异种移植物（PDXs）和类器官对BET抑制剂JQ1中等敏感。因此，在Q165P突变细胞中，AR，BRD4和下游效应子（例如RAC1和磷酸化的AKT）的蛋白质水平没有像F133V突变细胞中那样强烈升高。但是，NEO2734，BET和CBP / p300的新型双重抑制剂在体内和体外均对热点突变（F133V）和非热点突变（Q165P）PCa细胞均具有活性。这些数据为临床研究NEO2734在SPOP突变的PCa患者中的抗癌功效提供了有力的依据。