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Research Articles: Therapeutics, Targets, and Development

Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling

Departments of ¹ Breast Medical Oncology and ² Molecular and Cellular Oncology; ³ Breast Cancer Translational Research Laboratory, The University of Texas M. D. Anderson Cancer Center; and ⁴ The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Rita Nahta or Francisco J. Esteva, Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-792-2817; Fax: 713-563-0739. E-mail: rnahta{at}mdanderson.org or festeva{at}mdanderson.org

Abstract

The majority of breast cancer patients who achieve an initial therapeutic response to the HER2-targeted antibody trastuzumab will show disease progression within 1 year. Thus, the identification of novel agents that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical. In the current study, we show that the dual epidermal growth factor receptor (EGFR)/human EGFR-2 (HER2) kinase inhibitor lapatinib induces apoptosis in trastuzumab-resistant cells derived from the HER2-overexpressing SKBR3 breast cancer line. Lapatinib inhibited EGFR and HER2 signaling in resistant cells, blocking activation of downstream Akt, mitogen-activated protein kinase, and S6 kinases and inducing expression of p27kip1. Importantly, lapatinib also inhibited insulin-like growth factor I (IGF-I) signaling and growth-promoting effects in parental and resistant cells, and the cytotoxic effects of lapatinib were further enhanced by the IGF-I receptor–blocking antibody IR3. As increased IGF-I receptor signaling has been implicated in trastuzumab resistance, our data strongly support further study of lapatinib as a potential therapeutic in breast cancers that have progressed on trastuzumab. [Mol Cancer Ther 2007;6(2):667–74]

Grant support: National Cancer Institute grant K01CA118174 (R. Nahta), Breast Cancer Research Foundation (F.J. Esteva), University Cancer Foundation at The University of Texas M. D. Anderson Cancer Center (F.J. Esteva and R. Nahta), Nellie B. Connally Breast Cancer Research Fund, and NIH Cancer Center Support grant CA 16672-27 (Media Preparation Facility, Flow Cytometry and Cellular Imaging Facility).

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 7/19/06; revised 11/ 9/06; accepted 12/18/06.

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