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.
Highlights
SPOP gene encodes a substrate recognition subunit of the CULLIN3-RBX1 E3 ubiquitin ligase (CRL) complex (Zhuang et al, 2009)
Since NEO2734, a novel Bromodomain and extra-terminal domain (BET) and CBP/p300 dual inhibitor, offers a unique opportunity to explore the potential inhibition of both BET and CBP/p300 pathways with a single agent (Giles et al, 2018), we explored its activity in Q165P mutant prostate cancer (PCa) cells
Increasing evidence indicates that SPOP mutations often cause elevation of its degradation substrates including androgen receptor (AR) and transcriptional cofactors such as TRIM24, SRC3, and BET proteins (An et al, 2014; Geng et al, 2014; Groner et al, 2016; Blattner et al, 2017; Zhang et al, 2017)
Summary
SPOP (speckle-type POZ protein) gene encodes a substrate recognition subunit of the CULLIN3-RBX1 E3 ubiquitin ligase (CRL) complex (Zhuang et al, 2009). SPOP binding generally triggers the ubiquitination and proteasomal degradation of target proteins mediated by RBX1-dependent recruitment of E2 ubiquitin-conjugating enzyme into the CRL complex. Its mutations occur at a high frequency in a few specific residues (or so-called “hotspots”) in the MATH domain, such as F133V, W131R, and F102C (Barbieri et al, 2012; Cancer Genome Atlas Research Network, 2015; Armenia et al, 2018). It seems that SPOP mutations are loss-of-function missense mutations which a 2019 The Authors.
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