Localized high-risk prostate cancer harbors an androgen receptor low subpopulation susceptible to HER2 inhibition

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Localized high-risk prostate cancer presents challenges due to high recurrence rates.
• Neoadjuvant hormonal therapies aim to treat micrometastatic disease but require better baseline profiling for treatment response assessment.

Approach:

• Comprehensive gene expression profiling of 37 locally advanced prostate tumors before neoadjuvant androgen deprivation therapy (ADT) and enzalutamide treatment.
• Investigated the association between HER2 activity, androgen receptor (AR) activity, and treatment response.
• Validated findings using transcriptional profiling and immunohistochemistry on external patient cohorts.

Key Points:

• A HER2 activity transcriptional program correlated with poor outcomes and opposed AR activity in prostate cancer.
• Exceptional responders showed lower HER2 and phospho-HER2 levels.
• An inverse correlation between AR and HER2 activity was a consistent feature in aggressive prostate tumors.

Conclusions:

• Prostate tumors exhibit AR activity-low phenotypes prior to antiandrogen therapy, which can be exploited.
• AR activity-low, HER2 activity-high cells pre-exist and are resistant to ADT.
• Targeting HER2, alone or with enzalutamide, offers a therapeutic strategy for these resistant cells.