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[Cancer Research 63, 1-5, January 2003]
© 2003 American Association for Cancer Research

Perspectives in Cancer Research

Targeting the Epidermal Growth Factor Receptor in Cancer

Apoptosis Takes Center Stage1

Csaba Kari, Tung O. Chan, Marlene Rocha de Quadros and Ulrich Rodeck2

Department of Dermatology and Cutaneous Biology [C. K., M. R. d. Q., U. R.], and the Kimmel Cancer Center [T. O. C., U. R.], Thomas Jefferson University, Philadelphia, Pennsylvania 19130

ABSTRACT

Aberrant activation of the epidermal growth factor receptor (EGFR) is frequently observed in neoplasia,notably in tumors of epithelial origin. Attempts to treat such tumors with EGFR antagonists have met with remarkable initial successes, particularly when EGFR antagonists were used in combination with chemotherapy or ionizing radiation. Considering the almost ubiquitous expression of the EGFR in normal epithelial tissues, these clinical trials also revealed a surprisingly low rate of adverse side effects associated with EGFR blockade. This review highlights antiapoptotic effects of EGFR activation as they relate to therapeutic efficacy of EGFR blockade. We introduce the concept that control of cell survival through EGFR activation is conditional in the sense that it is rate limiting to tumor cell survival but not to survival of normal epithelial cells. Specifically, normal epithelial cells are provided with a full complement of physiological cell-cell contacts and cell-matrix interactions that lessen their dependence on survival signals provided by the EGFR. By contrast, malignant tumor cells faced with inadequate cell-matrix contacts critically depend on EGFR activation for survival, rendering them more susceptible to apoptosis induction by EGFR blockade. Redundant control of cell survival by the EGFR and extracellular matrix/cell adhesion receptors is enabled, in part, by shared signal transduction pathways that control expression and activation states of members of the Bcl-2 family of apoptosis regulators.




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Copyright © 2003 by the American Association for Cancer Research.