Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer

Area of Science:

• Oncology
• Cancer Biology
• Molecular Urology

Background:

• Hormonal therapy targeting the androgen receptor (AR) is a primary treatment for prostate cancer (PCa), but resistance eventually develops.
• Tumor cell heterogeneity, specifically the presence of AR-positive (AR+) luminal cells and AR-negative (AR-) neuroendocrine (NE) cells, is hypothesized to contribute to treatment failure.
• Understanding the mechanisms driving NE cell emergence and their role in therapy resistance is crucial for developing more effective treatments.

Purpose of the Study:

• To investigate the role of the cell surface receptor CXCR2 in the development and function of neuroendocrine prostate cancer (NEPC) cells.
• To explore the potential of targeting CXCR2 in combination with AR-targeting therapy to overcome treatment resistance in PCa.
• To elucidate the contribution of NE cells to the tumor microenvironment and their impact on AR+ luminal cell survival.

Main Methods:

• Purification of NE cells from primary human prostate adenocarcinoma using CXCR2 as a cell surface marker.
• Functional assays to assess the role of CXCR2 in driving the NE phenotype, including AR expression, lineage plasticity, and hormonal therapy resistance.
• Evaluation of a combined CXCR2 inhibition and AR targeting strategy in preclinical mouse xenograft models of PCa.

Main Results:

• CXCR2 was successfully identified as a marker for purifying NE cells from human prostate adenocarcinoma.
• CXCR2 was confirmed to drive the NE phenotype, characterized by loss of AR expression, lineage plasticity, and resistance to hormonal therapy.
• CXCR2-expressing NE cells were found to create a supportive tumor microenvironment for AR+ luminal cells, contributing to overall tumor progression and therapy resistance.
• Combination therapy targeting both CXCR2 and AR demonstrated significant efficacy in reducing tumor growth in mouse xenograft models.

Conclusions:

• CXCR2 plays a critical role in the emergence and function of neuroendocrine prostate cancer cells.
• Targeting CXCR2, in conjunction with standard AR-targeting therapies, represents a promising strategy to overcome treatment resistance in heterogeneous prostate cancer.
• This therapeutic approach has the potential to address treatment failure caused by the complex interplay between different tumor cell populations in prostate cancer.