Evaluating PI3K/AKT inhibitors’ sensitivity in prostate cancer cell lines harboring androgen receptor gene rearrangements

Abstract

Prostate cancer, particularly its advanced form known as castration-resistant prostate cancer (CRPC), continues to pose significant clinical challenges. The persistence and progression of CRPC are often driven by the androgen receptor (AR) reactivation, even under conditions of androgen deprivation. This study focuses on the PI3K/AKT pathway, a critical oncogenic driver in prostate cancer is often activated in tumors with AR gene structural rearrangements (AR-GSRs) due to loss of PTEN function. This thesis evaluates the hypothesis that the PI3K/AKT pathway could serve as an effective therapeutic target in CRPC cell lines harboring AR-GSRs, given its role in bypassing the androgen signaling cascade and independently promoting tumor survival and proliferation. Using prostate cancer cell lines engineered to express specific AR-GSRs, this research employed crystal violet growth assays to determine the sensitivity of cells to PI3K/AKT inhibitors. The findings reveal that cell lines with AR-GSRs display a distinct response to PI3K/AKT pathway inhibition compared to those without these rearrangements. Specifically, cells lacking the ligand-binding domain of AR due to gene rearrangements showed increased sensitivity to PI3K/AKT inhibitors, suggesting a potential therapeutic advantage in targeting this pathway. This thesis provides insight into the complex interactions between AR signaling and the PI3K/AKT pathway. It suggests a targeted therapeutic strategy that may enhance treatment outcomes in CRPC patients with specific genomic alterations. These findings could guide the development of personalized medicine approaches in the treatment of prostate cancer, particularly for those resistant to conventional therapies.