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The Future of ErbB-1 and ErbB-2 Pathway Inhibition in Breast Cancer: Targeting Multiple Receptors

Division of Hematology-Oncology, David Geffen School of Medicine at The University of California Los Angeles, Los Angeles, California, USA

Correspondence: Dennis J. Slamon, M.D., Ph.D., Department of Medicine, Hematology & Oncology, 3360 Ueberroth Building, Mail Code 707707, Los Angeles, California 90095-7077, USA. Telephone: 310-825-5193; Fax: 310-267-2310; e-mail: dslamon{at}mednet.ucla.edu

Key Words. Targeted therapy • Dual ErbB inhibition • Signaling pathways • Tyrosine kinase inhibitors • Lapatinib • Trastuzumab • Estrogen receptors

There is great enthusiasm in the oncology community over the discovery and use of molecules targeting cellular signaling processes. These processes are essential to cellular functions, including proliferation and differentiation. Many malignancies are characterized by abnormalities in cellular signal transduction, with dysfunction or overexpression of growth factor receptors or other elements of signaling pathways potentially resulting in increased cell survival, proliferation, invasion potential, metastasis, and angiogenesis [1, 2]. This enthusiasm is warranted, despite the fact that it has been tempered by apparent failure in the therapeutic application of some of the molecular-targeted therapies that have been developed. Clear evidence of the promise and success of this approach has been provided in studies of molecules for which we know the target to be operational in the pathogenesis of malignancy and for which drug delivery results in access to and interaction with the target sufficient to provide a pharmacologic effect. It seems likely that many of the apparent failures in therapeutic application are the result of an inability to identify appropriate patient populations—that is, those with target aberrations that are causally sufficient for expression of disease. These failures underscore the need for a better understanding of patient and disease characteristics that increase the likelihood of therapeutic response, as well as a better understanding of how the targeted signaling pathways act individually and interact with one another in the pathogenesis of the disease in which they are being evaluated.

Figure 1 provides a simplified schematic of some cell signaling pathways involved in proliferation, transformation, apoptosis, motility, and metastasis and selected molecular-targeted agents that have been developed to inhibit the signaling that induces these processes. What is not made clear in such simplified schematics is that many signaling pathways appear to constitute a highly integrated network rather than a simple linear structure down a single pathway. This allows for considerable crosstalk, networking, and redundancy among pathways in cell signaling. Thus, inhibition of particular receptors known to activate certain pathways may still not result in complete or even significant inhibition of signaling or cell activation. One of the many issues to be confronted in the application of molecular-targeted therapies is whether broader target specificity is more likely to be successful than narrower targeting. Agents have been developed that inhibit the tyrosine kinases of both the ErbB-1 (epithelial growth factor receptor [EGFR]) and ErbB-2 (HER-2) epithelial growth factor receptors, the overexpression/overactivation of which is associated with increased proliferation and survival of a variety of human neoplasms [3, 4]. As shown in Figure 2, lapatinib (GlaxoSmithKline; Research Triangle Park, NC), one of these new agents, exhibits greater activity against ErbB-2⁺ breast cancer cell lines than the anti-HER-2 monoclonal antibody trastuzumab (Herceptin^®; Genentech, Inc.; South San Francisco, CA), and likewise, exhibits activity against trastuzumab-conditioned or partially resistant cells (D. Slamon, M.D., Ph.D., unpublished data). Such findings suggest considerable merit in the dual tyrosine kinase inhibition approach.

View larger version (29K): [in this window] [in a new window]   Figure 1. Schematic of tumor cell (TC) and endothelial cell (EC) signaling pathways targeted by select molecular-targeted therapies. VEGF = vascular endothelial growth factor; PIGF = placental growth factor.

View larger version (16K): [in this window] [in a new window]   Figure 2. Effectiveness of trastuzumab and the dual ErbB-1 (EGFR) and ErbB-2 tyrosine kinase inhibitor lapatinib at inhibiting MDA-MB-361 and MCF7 human breast cancer cells with or without trastuzumab conditioning compared with controls. (Unpublished data, D. Slamon, M.D., Ph.D.).

This supplement features reviews of some of the targeted therapy approaches to treatment of breast cancer. Dr. Francisco J. Esteva (The University of Texas; M.D. Anderson Cancer Center; Houston, TX) reviews the characteristics of monoclonal antibody erbB inhibitors, small-molecule erbB tyrosine kinase inhibitors, and potential vaccines targeting a number of mechanisms involved in breast cancer pathogenesis, providing an overview of the ongoing progress in the clinical development of targeted therapies.

Dr. Howard A. Burris III (Sarah Cannon Cancer Center; Nashville, TN) reviews the rationale for the development of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib. As indicated above, this agent has shown greater biologic activity than single-target tyrosine kinase inhibitors. A phase I study of the agent in patients with solid tumors indicates that it is safe and well tolerated and has provided evidence of clinical activity, including stable disease in several patients remaining on study for more than 4 months, minor response, and a complete response in a patient remaining on study for >19 months. A phase IB study of the agent in patients with previously treated metastatic cancers indicates clinical activity in various tumors, including partial responses in patients with trastuzumab-refractory metastatic breast cancer. Assessment of biologic correlates indicates that increased apoptosis, as measured by the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay, is correlated with clinical response. Lapatinib is currently being evaluated in a number of phase II and III trials in patients with advanced breast cancer.

Dr. Kathy D. Miller (Indiana University School of Medicine; Indianapolis, IN) reviews data suggesting that resistance to erbB-2 inhibitors (e.g., trastuzumab), in erbB-2⁺ tumors can be overcome by inhibition of erbB-1. Preclinical studies indicate synergistic effects of erbB-1 and erbB-2 inhibitors in the setting of erbB-2 overexpression and suggest the potential for preventing or delaying resistance using a dual inhibition approach. Studies assessing the pharmacodynamic and clinical effects of combining trastuzumab with erbB inhibitors are under way.

Dr. Matthew Ellis (Siteman Cancer Center; Washington University; St. Louis, MO) discusses prospects for the combined inhibition of erbB-1 or erbB-2 and estrogen receptors to overcome the resistance to endocrine therapy associated with erbB overexpression/activation in the setting of hormone-receptor-positive status. Preliminary findings of a phase II study of letrozole (Femara^®; Novartis Pharmaceuticals Corporation; East Hanover, NJ), and trastuzumab suggest restoration of endocrine therapy efficacy in patients with erbB-2⁺ and receptor-positive advanced disease. A number of advanced phase trials combining endocrine therapy with erbB inhibitors are being conducted.

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