© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 24, 1829,
December 19, 2001
© 2001 Oxford University Press
MEMORANDUM FOR: Science Writers and Editors on the Journal Press List
Insulin-Like Growth Factor Receptors May Be Involved in Development of Resistance to the Breast Cancer Drug Herceptin
December 13, 2001 (EMBARGOED FOR RELEASE 4 P.M. EST December 18)
New research suggests that insulin-like growth factor-I (IGF-I) receptors may be involved in the development of resistance to the breast cancer drug Herceptin.
Herceptin (Genentech, San Francisco) is a monoclonal antibody that has important therapeutic activity against breast cancers that overexpress the protein HER2. However, most breast cancers develop a resistance to Herceptin in less than a year through mechanisms that are poorly understood. Yuhong Lu, M.D., and Michael Pollak, M.D., Jewish General Hospital and McGill University, Montreal, Canada, and colleagues found that an increased level of IGF-I receptor (IGF-IR) signaling appears to interfere with Herceptin action. Therefore, they believe that strategies that target IGF-IR signaling may prevent or delay development of resistance to Herceptin. These results appear in the Dec. 19 issue of the Journal of the National Cancer Institute.
The authors investigated the ability of Herceptin to inhibit the growth of two different breast cancer cell lines. One of these cells lines—MCF-7/HER2-18—overexpresses HER2/neu receptors and expresses IGF-IRs. When these cells were grown under conditions where IGF-I signaling was minimized, Herceptin reduced cell proliferation by 42%. However, in the presence of IGF-I, Herceptin failed to inhibit proliferation.
In SKBR3 cells, which overexpress HER2/neu receptor but express few IGF-IRs, Herceptin reduced proliferation by 42%. This reduction was independent of IGF-I concentration. When SKBR3 cells were genetically altered to overexpress IGF-IRs and cultured with IGF-I, Herceptin had no effect on proliferation. However, the addition of IGF-binding protein-3, which decreased IGF-IR signaling, restored Herceptin-induced growth inhibition.
These results add to the evidence that the IGF-IR pathway is an attractive molecular target in anticancer drug development and deserves study in the context of the clinically important challenge of extending the usefulness of Herceptin. However, the authors urge the establishment of banks of sequential tumor biopsy specimens to determine if changes in signal transduction (particularly IGF-IR signaling) associated with the development of resistance to Herceptin or other drugs in patients correlate with these and other laboratory findings.
In an editorial, Joan Albanell, M.D., and Jose Baselga, M.D., Vall d’Hebron University Hospital, Barcelona, Spain, note that the mechanisms of action of Herceptin and the causes of resistance to this antibody warrant further investigation. They say that the study by Lu et al. points to a potential strategy—the inhibition of IGF-IR signaling—to prevent or reverse resistance to Herceptin. If a correlation between IGF-IR activation and resistance to Herceptin were established in the clinic, it would be a strong signal to combine anti-IGF-IR and anti-HER2 therapies in patients with breast cancer.
Contact: Glenn Nashen, Jewish General Hospital, McGill University, (514) 340-8222, ext. 4818; fax: (514) 340-8135; gnashen{at}adm.jgh.mcgill.ca. Editorial: Núria Llistar Verdú, Vall d’Hebron Hospital, Barcelona, Spain, 34 3 489 44 35; fax: 34 3 489 40 14; nllistar{at}cs.vhebron.es.
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Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001;93:1852–7.
Editorial: Albanell J, Baselga J. Unraveling resistance to trastuzumab (Herceptin): Insulin-like growth factor-I receptor, a new suspect. J Natl Cancer Inst 2001;93:1830–2.
Note: This memo to reporters is from the Journal staff and is not an official release of the National Cancer Institute (NCI) or Oxford University Press (OUP) nor does it reflect NCI or OUP policy. In addition, unless otherwise stated, all articles and items published in the Journal reflect the individual views of the authors and not necessarily the official points of view held by NCI, any other component of the U.S. government, OUP, or the organizations with which the authors are affiliated. Neither NCI nor any other component of the U.S. government nor OUP assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein.
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