Increased ErbB2 Signaling Is an Early Adaptation to Androgen Signaling Inhibition and Persists in...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• ErbB2 (Human Epidermal growth factor Receptor 2) activity is elevated in some prostate cancers (PCa).
• Mechanisms driving this increased ErbB2 activity and its role in prostate cancer progression to castration-resistant prostate cancer (CRPC) are not fully understood.

Purpose of the Study:

• To identify mechanisms responsible for increased ErbB2 activity in prostate cancer.
• To investigate the role of these mechanisms in the progression to castration-resistant prostate cancer.

Main Methods:

• Utilized immunohistochemistry (IHC), reverse-phase protein array, and RNA sequencing.
• Interrogated ErbB2 signaling in cell lines, xenografts, and clinical tumors at various stages of castration resistance.
• Assessed sensitivity to ErbB2 inhibitors (neratinib) in vitro and in vivo.

Main Results:

• ErbB2 activation was observed in ~26% of tumors post-androgen signaling inhibition (ASI) and in advanced CRPC.
• The NRG1 ligand was found in ~75% of tumors treated with neoadjuvant ASI, with rapid increases in NRG1 mRNA upon ASI.
• An active ERBB2 splice variant (d16ERBB2) was also rapidly upregulated by ASI and detected in a subset of CRPC.
• ErbB2 signaling remained sensitive to neratinib, which enhanced castration responses and inhibited castration-resistant xenograft growth.

Conclusions:

• Increased ErbB2 signaling is an early adaptation to ASI, contributing to castration resistance in prostate cancer.
• Upregulation of NRG1 and d16ERBB2 are key mechanisms driving increased ErbB2 signaling.
• ErbB2 antagonists may enhance ASI efficacy in castration-sensitive PCa, and phosphorylated ErbB2 could serve as a predictive biomarker for CRPC treatment response.