AKT1 and Familial prostate cancer: Interestingly, in prostate cancer, increased PI3K/AKT signaling has been implicated in primary resistance to BETi, which is driven through mutations in the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) that increased BRD4 protein levels due to impaired SPOP-mediated degradation53.