Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) links ERG expression to androgen receptor (AR) regulation.
• T:E fusion is associated with PTEN loss and decreased INPP4B, potentially compensating for ERG's suppression of AKT signaling.

Purpose of the Study:

• To investigate the role of ERG in suppressing AKT signaling in PCa.
• To determine if AR inhibition impacts AKT activity in T:E fusion-positive PCa.
• To assess the therapeutic implications of AKT activation in T:E fusion PCa.

Main Methods:

• Confirmation of ERG-mediated suppression of IRS2 and AKT activation in PCa cells and a mouse model.
• Analysis of INPP4B expression changes upon ERG downregulation.
• Evaluation of AKT activity in a T:E fusion-positive patient-derived xenograft (PDX) model after androgen deprivation.
• Assessment of AKT activation in clinical trial data from neoadjuvant AR inhibition.

Main Results:

• ERG was confirmed to suppress IRS2 and AKT activation in PCa.
• Decreased INPP4B expression in T:E fusion tumors appears to be an indirect effect of selective pressure.
• Androgen deprivation led to increased AKT activity in a T:E fusion-positive PDX model.
• Clinical trials showed greater AKT activation increases in T:E fusion-positive tumors following AR inhibition.

Conclusions:

• AKT activation may reduce the effectiveness of AR-targeted therapy in T:E fusion PCa.
• Patients with T:E fusion PCa may benefit from combination therapy targeting both AR and AKT.
• Understanding the interplay between ERG, AR, and AKT is crucial for optimizing PCa treatment strategies.