Amiloride Sensitizes Prostate Cancer Cells to the Reversible Tyrosine Kinase Inhibitor Lapatinib by Modulating ERBB3...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Neoadjuvant therapy (NAT) in prostate cancer (PCa) aims to improve radical prostatectomy (RP) outcomes by reducing tumor burden.
• Current NAT using androgen deprivation risks castration-resistant PCa (CRPC) and significant side effects.
• Epidermal growth factor receptor (EGFR) family members, HER2 and ErbB3, are implicated in PCa progression.

Purpose of the Study:

• To identify alternative NAT for hormone-sensitive prostate cancer (HSPC) that avoids androgen receptor (AR) transcriptional activity.
• To investigate the mechanism of lapatinib resistance in PCa and explore combination strategies.

Main Methods:

• Investigated the role of ErbB3 nuclear localization in lapatinib resistance.
• Tested the effect of amiloride hydrochloride on ErbB3 localization and HER2/ErbB3 dimerization.
• Assessed the efficacy of amiloride combined with lapatinib on apoptosis and AR activity in HSPC models.

Main Results:

• ErbB3 localizes to the nucleus in HSPC, protecting it from lapatinib.
• Amiloride prevents ErbB3 nuclear localization, promoting membrane-localized HER2/ErbB3 dimer formation.
• Amiloride plus lapatinib combination therapy effectively increased apoptosis and inhibited downstream AKT/ERK signaling without affecting AR activity.

Conclusions:

• Amiloride and lapatinib combination therapy represents a potential NAT strategy for localized PCa.
• This combination targets HSPC by disrupting HER2/ErbB3 signaling without the adverse effects of androgen deprivation.
• Further studies are warranted to explore this combination as a viable treatment option for prostate cancer.