Journal Article

Amiloride sensitizes prostate cancer cells to the reversible tyrosine kinase inhibitor lapatinib by modulating Erbb3 subcellular localization

Jathal, Maitreyee K., Mudryj, Maria, Dall’Era, Marc A., Ghosh, Paramita M.

2025

Overview

Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by ‘debulking’ of high-risk PCa; however, using androgen deprivation therapy (ADT) at this point risks castration resistant PCa (CRPC) clonal proliferation. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated potassium-sparing diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated ERK1/2 and inhibited survival. Amiloride combined with lapatinib significantly increased apoptosis at relatively low doses of both drugs but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with using ADT as NAT in HSPC.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Amiloride / Amiloride - pharmacology / Androgen receptors / Androgens / Antineoplastic Agents - pharmacology / Apoptosis / Biochemistry / Biomedical and Life Sciences / Biomedicine / Castration / Cell Biology / Cell Line, Tumor / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Cell Proliferation - drug effects / Dimers / Diuretics / Epidermal growth factor receptors / ErbB-2 protein / ErbB-3 protein / Extracellular signal-regulated kinase / family / Growth factors / Humans / Inhibitor drugs / Kinases / Lapatinib - pharmacology / Life Sciences / Localization / Male / Membranes / Original Article / plasma membrane / Prostate cancer / Prostatectomy / prostatic neoplasms / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Protein Kinase Inhibitors - pharmacology / Receptor, ErbB-2 - metabolism / Receptor, ErbB-3 - antagonists & inhibitors / Receptor, ErbB-3 - metabolism / Receptors / Receptors, Androgen - metabolism / Targeted cancer therapy / transcription (genetics) / Transcription activation / Tyrosine / Tyrosine Kinase Inhibitors