Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Resistant Growth

Abstract

Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report <i>PIK3CA</i> mutation/amplification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate <i>Pik3ca</i> in mouse prostate epithelium. We show <i>Pik3ca</i>^H1047R mutation causes p110α-dependent invasive prostate carcinoma <i>in vivo</i> Furthermore, we report that <i>PIK3CA</i> mutation and <i>PTEN</i> loss coexist in patients with prostate cancer and can cooperate <i>in vivo</i> to accelerate disease progression via AKT-mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant <i>Pik3ca</i> mutation and <i>Pten</i> loss caused <i>de novo</i> CRPC. Thus, <i>Pik3ca</i> mutation and <i>Pten</i> deletion are not functionally redundant. Our findings indicate that <i>PIK3CA</i> mutation is an attractive prognostic indicator for prostate cancer that may cooperate with <i>PTEN</i> loss to facilitate CRPC in patients.<b>Significance:</b> We show <i>PIK3CA</i> mutation correlates with poor prostate cancer prognosis and causes prostate cancer in mice. Moreover, <i>PIK3CA</i> mutation and <i>PTEN</i> loss coexist in prostate cancer and can cooperate <i>in vivo</i> to accelerate tumorigenesis and facilitate CRPC. Delineating this synergistic relationship may present new therapeutic/prognostic approaches to overcome castration/PI3K-AKT-mTORC1/2 inhibitor resistance. <i>Cancer Discov; 8(6); 764-79. ©2018 AACR.</i><i>See related commentary by Triscott and Rubin, p. 682</i><i>This article is highlighted in the In This Issue feature, p. 663</i>.