Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo

Authors

C L. Schwab, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
S Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
D P. English, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
D M. Roque, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
S Lopez, Division of Gynecologic Oncology, University Campus Biomedico of Roma, Via Álvaro del Portillo, 21, 00128 Rome, Italy.
E Cocco, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
R Nicoletti, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
I Bortolomai, Telethon Institute for Gene Therapy (TIGET), Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy.
E Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
E Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
D-A Silasi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
M Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
P E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
T J. Rutherford, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
A D. Santin, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.

Document Type

Article

Publication Title

British journal of cancer

Abstract

BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 μM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 μM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.

First Page

1750

Last Page

6

DOI

10.1038/bjc.2014.519

Publication Date

10-28-2014

Recommended Citation

Schwab, C L.; Bellone, S; English, D P.; Roque, D M.; Lopez, S; Cocco, E; Nicoletti, R; Bortolomai, I; Bonazzoli, E; Ratner, E; Silasi, D-A; Azodi, M; Schwartz, P E.; Rutherford, T J.; and Santin, A D., "Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo" (2014). Obstetrics and Gynecology. 72.
https://scholar.bridgeporthospital.org/obgyn/72

Identifier

25268372 (pubmed); PMC4453741 (pmc); 10.1038/bjc.2014.519 (doi); bjc2014519 (pii)