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Updated: Jan 23, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing

Maitreyee K Jathal1, Thomas M Steele1, Salma Siddiqui2

  • 1Department of Urology, University of California Davis, Sacramento, CA, United States.

British Journal of Cancer
|June 19, 2019
PubMed
Abstract

Insights

Lapatinib resistance in prostate cancer is linked to increased HER2 protein stability. The pan-ErbB inhibitor dacomitinib overcomes this resistance by targeting the EGFR axis, offering a viable therapeutic option.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Overexpression of the ErbB family (EGFR/HER2/ErbB3/ErbB4) is common in castration-resistant prostate cancer (CRPC).
  • Lapatinib, a dual EGFR/HER2 inhibitor, showed limited success in Phase II trials for CRPC, necessitating investigation into resistance mechanisms.

Purpose of the Study:

  • To investigate the mechanisms underlying lapatinib resistance in CRPC.
  • To determine if alternative ErbB inhibitors can overcome lapatinib resistance and be effective in CRPC treatment.

Main Methods:

  • Utilized the CWR22 human tumor xenograft and its CRPC subline 22Rv1.
  • Analyzed sera from CRPC patients treated with lapatinib from a Phase II trial.
  • Conducted mechanistic studies in LNCaP, C4-2, and 22Rv1 cell lines.

Main Results:

  • Lapatinib treatment led to increased intratumoral HER2 protein levels, promoting resistance in mouse models and observed in patient sera.
  • Lapatinib enhances HER2 protein stability, leading to membrane localization, EGFR/HER2 heterodimerization, and increased cell viability.
  • Knockdown of HER2 and ErbB3, but not EGFR, sensitized CRPC cells to lapatinib.
  • Dacomitinib, an irreversible pan-ErbB inhibitor, reduced HER2 stability, prevented ErbB membrane localization and heterodimerization, decreased signaling, and induced apoptosis.

Conclusions:

  • Targeting the EGFR axis with the irreversible pan-ErbB inhibitor dacomitinib presents a viable therapeutic strategy for CRPC.
  • Dacomitinib demonstrates efficacy in overcoming lapatinib resistance mechanisms in CRPC models.

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