This study reveals the association between baseline HER2 activity and resistance to neoadjuvant androgen deprivation therapy (ADT) in localized high-risk prostate cancer. It identifies that the HER2-high/AR-low subpopulation is sensitive to HER2 inhibitors, and combining HER2 inhibitors with enzalutamide significantly enhances tumor cell killing, offering potential therapeutic targets for clinical treatment.
Literature Overview
This article, titled 'Localized high-risk prostate cancer harbors an androgen receptor activity–low subpopulation susceptible to HER2 inhibition', published in The Journal of Clinical Investigation, reviews and summarizes the molecular mechanisms underlying resistance to neoadjuvant androgen deprivation therapy (ADT) in high-risk localized prostate cancer. It further demonstrates the negative correlation between elevated HER2 activity and reduced androgen receptor (AR) activity through transcriptomic, protein expression, and cell function experiments, suggesting that HER2 inhibitors may target this resistant subpopulation and offer new strategies for clinical treatment.
Background Knowledge
Localized high-risk prostate cancer is a type with a high recurrence rate. Despite receiving neoadjuvant androgen deprivation therapy (ADT) and anti-androgen treatments such as enzalutamide, a significant proportion of patients still develop resistance to therapy. Current research indicates that the androgen receptor (AR) is the primary driver of prostate cancer, and therapies targeting AR, such as ADT or enzalutamide, are effective in most cases. However, resistance remains a major clinical challenge. Understanding the molecular mechanisms behind this resistance is critical for developing novel therapeutic approaches.
Research Methods and Experiments
The study enrolled 37 patients with localized high-risk prostate cancer who received neoadjuvant ADT combined with enzalutamide. A total of 48 MRI-visible lesions were collected, and the gene expression profiles of 147 tumor lesions were analyzed using laser capture microdissection (LCM) and transcriptomic sequencing. Residual Cancer Burden (RCB) was used as the primary endpoint, and the results were further analyzed in conjunction with PTEN loss, TMPRSS2:ERG status, and HER2/AR immunohistochemical data. Additionally, the findings were validated using an external transcriptomic cohort (n=121) and a multiplex immunohistochemistry cohort (n=61). In cellular experiments, LNCaP cells were stimulated with EGF and NRG-1 to assess HER2 phosphorylation and the impact of AR inhibitors on ERBB2 expression.
Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to identify elevated HER2 activity as a molecular marker for resistance to neoadjuvant ADT in localized high-risk prostate cancer. It also highlights the potential of HER2 as a druggable biomarker. Future clinical trials should evaluate the efficacy of combining HER2 inhibition with AR blockade in treating localized high-risk prostate cancer to improve patient outcomes.
Conclusion
This study systematically analyzed the interplay between HER2 activity and AR signaling pathways in localized high-risk prostate cancer. It identified HER2 expression as a predictive biomarker for response to neoadjuvant ADT. Further findings demonstrate that HER2 inhibitors exert stronger anti-tumor effects in AR-low cells and that combination therapy significantly enhances cell killing. These results provide new molecular targets for prostate cancer treatment and suggest that HER2 testing should be incorporated into risk assessment for high-risk patients. In the future, HER2-directed therapies may represent a crucial strategy for improving outcomes in patients with localized high-risk prostate cancer.
