@article{7a3bd4fe6f4c4926963d02f1c6572672,
title = "The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer",
abstract = "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.",
keywords = "BRD4, CBP/p300, NEO2734, SPOP, prostate cancer",
author = "Yuqian Yan and Jian Ma and Dejie Wang and Dong Lin and Xiaodong Pang and Shangqian Wang and Yu Zhao and Lei Shi and Hui Xue and Yunqian Pan and Jun Zhang and Claes Wahlestedt and Giles, {Francis J.} and Yu Chen and Gleave, {Martin E.} and Collins, {Collin C.} and Dingwei Ye and Yuzhuo Wang and Haojie Huang",
note = "Funding Information: This work was supported in part by grants from the National Institutes of Health (CA134514, CA130908, CA193239, and CA203849 to H.H.), the Mayo Clinic Foundation (to H.H.), Epigene Therapeutics Inc (to H.H.), the Canadian Institutes of Health Research operating grants (141635, 144159, and 153081 to Y.W.), Terry Fox Research Institute program project (1062 to Y.W.), and the National Natural Science Foundation of China (81672544 and 81872099 to D.Y.). The authors would like to thank Epigene Therapeutics Inc for providing the compound NEO2734. Funding Information: This work was supported in part by grants from the National Institutes of Health (CA134514, CA130908, CA193239, and CA203849 to H.H.), the Mayo Clinic Foundation (to H.H.), Epigene Therapeutics Inc (to H.H.), the Canadian Institutes of Health Research operating grants (141635, 144159, and 153081 to Y.W.), Terry Fox Research Institute program project (1062 to Y.W.), and the National Natural Science Foundation of China (81672544 and 81872099 to D.Y.). The authors would like to thank Epigene Therapeutics Inc for providing the compound NEO2734. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2019",
month = nov,
day = "7",
doi = "10.15252/emmm.201910659",
language = "English (US)",
volume = "11",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "11",
}