The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

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. Synopsis While patient‐derived xenografts (PDXs) and organoids harboring the novel SPOP mutant Q165P respond modestly to the BET inhibitor JQ1, both Q165P mutant and JQ1‐resistant SPOP hotspot mutant prostate cancer cells are sensitive to the BET and CBP/p300 dual inhibitor NEO2734 in vitro and in vivo . Identification of a novel SPOP Q165P heterozygous mutation in primary and homozygous mutation in metastatic prostate cancer. Q165P likely causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Q165P mutant patient‐derived xenografts (PDXs) and organoids respond modestly to JQ1 and robustly to the BET and CBP/p300 dual inhibitor NEO2734. JQ1‐resistant SPOP hotspot mutant prostate cancer cells are sensitive to NEO2734 in vitro and in vivo . Graphical Abstract While patient‐derived xenografts (PDXs) and organoids harboring the novel SPOP mutant Q165P respond modestly to the BET inhibitor JQ1, both Q165P mutant and JQ1‐resistant SPOP hotspot mutant prostate cancer cells are sensitive to the BET and CBP/p300 dual inhibitor NEO2734 in vitro and in vivo .