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Research Articles: Therapeutics, Targets, and Development

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

¹ Cancer Research UK, Clinical Cancer Centre, University of Edinburgh, Edinburgh, United Kingdom and ² Roche Diagnostics GmbH, Penzberg, Germany

Requests for reprints: Simon Langdon, Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, United Kingdom. Phone: 44-131-777-3537; Fax: 44-131-777-3520. E-mail: simon.langdon{at}cancer.org.uk

Abstract

Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin ß1 (HRGß1) or transforming growth factor-, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGß1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-–stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGß1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGß1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGß1-enhanced phosphorylation of HER2 (Tyr⁸⁷⁷) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease. [Mol Cancer Ther 2007;6(1):93–100]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/11/06; revised 10/21/06; accepted 11/27/06.