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Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage
Csaba Kari1, Tung O Chan, Marlene Rocha de Quadros
1Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19130, USA.
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.
Insights
Epidermal growth factor receptor (EGFR) antagonists show promise in treating epithelial cancers by selectively targeting tumor cell survival pathways. This approach leverages the conditional dependence of cancer cells on EGFR for survival, minimizing side effects in normal tissues.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Aberrant activation of the epidermal growth factor receptor (EGFR) is common in epithelial cancers.
- EGFR antagonists have shown initial success in combination therapies for these tumors.
- EGFR is widely expressed in normal tissues, yet blockade shows low toxicity.
Purpose of the Study:
- To review the antiapoptotic effects of EGFR activation in relation to EGFR antagonist efficacy.
- To introduce the concept of conditional control of cell survival by EGFR.
- To explain the differential dependence of tumor versus normal cells on EGFR for survival.
Main Methods:
- Review of existing literature on EGFR signaling, apoptosis, and cancer therapy.
- Analysis of signal transduction pathways shared by EGFR and cell adhesion receptors.
- Examination of the role of Bcl-2 family proteins in apoptosis regulation.
Main Results:
- EGFR activation is conditionally rate-limiting for tumor cell survival but not normal epithelial cell survival.
- Normal cells rely less on EGFR due to robust cell-cell and cell-matrix interactions.
- Malignant cells with poor matrix contacts critically depend on EGFR, increasing susceptibility to apoptosis induction upon blockade.
- Shared signaling pathways involving Bcl-2 family regulators enable redundant cell survival control.
Conclusions:
- EGFR blockade efficacy is linked to the conditional dependence of tumor cells on EGFR for survival.
- Differential dependence on EGFR signaling between normal and malignant cells underlies the low toxicity of EGFR antagonists.
- Understanding these survival mechanisms can optimize cancer therapeutic strategies.