The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer
The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer
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DOI：
10.15252/emmm.201910659
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发表时间：
2019-09
影响因子：
11.1
通讯作者：
Yuqian Yan;Jian Ma;Dejie Wang;D. Lin;Xiaodong Pang;Shangqian Wang;Yu Zhao;Lei Shi;Hui Xue
中科院分区：
文献类型：
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作者：
Yuqian Yan;Jian Ma;Dejie Wang;D. Lin;Xiaodong Pang;Shangqian Wang;Yu Zhao;Lei Shi;Hui Xue
基于CULLIN3的E3泛素连接酶底物结合接头基因SPOP在前列腺癌（PCa）中经常发生突变。含有SPOP热点突变体（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，我们在原发性和转移性前列腺癌患者的SPOP MATH结构域边缘发现了一个以前未被识别的突变Q165P。Q165P突变导致MATH结构域的结构改变，损害SPOP二聚化和底物降解。与F133V热点突变肿瘤不同，Q165P突变患者来源的异种移植物（PDXs）和类器官对BET抑制剂JQ1具有中等敏感性。因此，与F133V突变体细胞相比，Q165P突变体细胞中AR、BRD4以及下游效应物如RAC1和磷酸化AKT的蛋白水平没有明显升高。然而，NEO2734是一种新型的BET和CBP/p300双抑制剂，在体外和体内均对热点突变体（F133V）和非热点突变体（Q165P） PCa细胞有活性。这些数据为临床研究NEO2734在SPOP突变的PCa患者中的抗癌效果提供了强有力的依据。
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.