For the first time, we show that PI3K relief of feedback inhibition is robust and therapeutically meaningful in the context of PTEN-loss but not in the setting of wild-type PTEN. In prostate cancers harboring loss of PTEN, this feedback inhibition is reciprocal between the p110 isoforms and occurs in the context of p110α or p110β-dominant signaling. Here, PIK3CD is linked to Familial prostate cancer.