Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Carlton L. Schwab; Diana P. English; Dana M. Roque; Stefania Bellone; Salvatore Lopez; Emiliano Cocco; Roberta Nicoletti; Thomas J. Rutherford; Peter E. Schwartz; Alessandro D. Santin

doi:10.1016/j.ygyno.2014.08.006

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Carlton L. Schwab, Diana P. English, Dana M. Roque, Stefania Bellone, Salvatore Lopez, Emiliano Cocco, Roberta Nicoletti, Thomas J. Rutherford, Peter E. Schwartz, Alessandro D. Santin

Fondazione IRCCS Istituto Nazionale dei Tumori

Research output: Contribution to journal › Article › peer-review

Abstract

Objectives. Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associatedwith USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primaryUSC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo.

Methods. HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro.Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo.

Results. HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011 μM ± 0.0008 vs. 0.312 μM ± 0.0456 p <0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p= 0.0019).

Conclusions. Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.

Original language	English
Pages (from-to)	142-148
Number of pages	7
Journal	Gynecologic Oncology
Volume	135
Issue number	1
DOIs	https://doi.org/10.1016/j.ygyno.2014.08.006
Publication status	Published - Oct 1 2014

Keywords

ErbB inhibitors
HER2/neu
Neratinib
Small tyrosine kinase inhibitors
Uterine serous carcinoma

ASJC Scopus subject areas

Obstetrics and Gynaecology
Oncology
Medicine(all)

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Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo. / Schwab, Carlton L.; English, Diana P.; Roque, Dana M.; Bellone, Stefania; Lopez, Salvatore; Cocco, Emiliano; Nicoletti, Roberta; Rutherford, Thomas J.; Schwartz, Peter E.; Santin, Alessandro D.

In: Gynecologic Oncology, Vol. 135, No. 1, 01.10.2014, p. 142-148.

Research output: Contribution to journal › Article › peer-review

Schwab, Carlton L. ; English, Diana P. ; Roque, Dana M. ; Bellone, Stefania ; Lopez, Salvatore ; Cocco, Emiliano ; Nicoletti, Roberta ; Rutherford, Thomas J. ; Schwartz, Peter E. ; Santin, Alessandro D. / Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo. In: Gynecologic Oncology. 2014 ; Vol. 135, No. 1. pp. 142-148.

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title = "Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo",

abstract = "Objectives. Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associatedwith USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primaryUSC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo.Methods. HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro.Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo.Results. HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011 μM ± 0.0008 vs. 0.312 μM ± 0.0456 p <0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p= 0.0019).Conclusions. Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.",

keywords = "ErbB inhibitors, HER2/neu, Neratinib, Small tyrosine kinase inhibitors, Uterine serous carcinoma",

author = "Schwab, {Carlton L.} and English, {Diana P.} and Roque, {Dana M.} and Stefania Bellone and Salvatore Lopez and Emiliano Cocco and Roberta Nicoletti and Rutherford, {Thomas J.} and Schwartz, {Peter E.} and Santin, {Alessandro D.}",

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T1 - Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

AU - Schwab, Carlton L.

AU - English, Diana P.

AU - Roque, Dana M.

AU - Bellone, Stefania

AU - Lopez, Salvatore

AU - Cocco, Emiliano

AU - Nicoletti, Roberta

AU - Rutherford, Thomas J.

AU - Schwartz, Peter E.

AU - Santin, Alessandro D.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Objectives. Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associatedwith USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primaryUSC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo.Methods. HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro.Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo.Results. HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011 μM ± 0.0008 vs. 0.312 μM ± 0.0456 p <0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p= 0.0019).Conclusions. Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.

AB - Objectives. Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associatedwith USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primaryUSC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo.Methods. HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro.Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo.Results. HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011 μM ± 0.0008 vs. 0.312 μM ± 0.0456 p <0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p= 0.0019).Conclusions. Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.

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