Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase

Maitreyee K. Jathal, Thomas M. Steele, Salma Siddiqui, Benjamin A. Mooso, Leandro S. D’Abronzo, Christiana M. Drake, Young E. Whang, Paramita M Ghosh

Research output: Contribution to journalArticle

Abstract

Background: Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed. Methods: The CWR22 human tumour xenograft and its CRPC subline 22Rv1 and sera from lapatinib-treated CRPC patients from a previously reported Phase II trial were used to study lapatinib resistance. Mechanistic studies were conducted in LNCaP, C4-2 and 22Rv1 cell lines. Results: Lapatinib increased intratumoral HER2 protein, which encouraged resistance to this treatment in mouse models. Sera from CRPC patients following lapatinib treatment demonstrated increased HER2 levels. Investigation of the mechanism of lapatinib-induced HER2 increase revealed that lapatinib promotes HER2 protein stability, leading to membrane localisation, EGFR/HER2 heterodimerisation and signalling, elevating cell viability. Knockdown of HER2 and ErbB3, but not EGFR, sensitised CRPC cells to lapatinib. At equimolar concentrations, the recently FDA-approved pan-ErbB inhibitor dacomitinib decreased HER2 protein stability, prevented ErbB membrane localisation (despite continued membrane integrity) and EGFR/HER2 heterodimerisation, thereby decreasing downstream signalling and increasing apoptosis. Conclusions: Targeting the EGFR axis using the irreversible pan-ErbB inhibitor dacomitinib is a viable therapeutic option for CRPC.

Original languageEnglish (US)
JournalBritish Journal of Cancer
DOIs
StatePublished - Jan 1 2019

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Castration
Prostatic Neoplasms
Protein Stability
Membranes
PF 00299804
lapatinib
Phase II Clinical Trials
Serum
Heterografts
Cell Survival
Therapeutics
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase. / Jathal, Maitreyee K.; Steele, Thomas M.; Siddiqui, Salma; Mooso, Benjamin A.; D’Abronzo, Leandro S.; Drake, Christiana M.; Whang, Young E.; Ghosh, Paramita M.

In: British Journal of Cancer, 01.01.2019.

Research output: Contribution to journalArticle

Jathal, Maitreyee K. ; Steele, Thomas M. ; Siddiqui, Salma ; Mooso, Benjamin A. ; D’Abronzo, Leandro S. ; Drake, Christiana M. ; Whang, Young E. ; Ghosh, Paramita M. / Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase. In: British Journal of Cancer. 2019.
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AU - Steele, Thomas M.

AU - Siddiqui, Salma

AU - Mooso, Benjamin A.

AU - D’Abronzo, Leandro S.

AU - Drake, Christiana M.

AU - Whang, Young E.

AU - Ghosh, Paramita M

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