TY - JOUR
AU - Lawrence, Theodore S.
AB - The epidermal growth factor receptor (EGFR) is now recognized as an important target for therapeutic interventions in many types of cancer. Because of the prognostic significance of EGFR expression in cancer and the laboratory data that provide direct evidence for aberrant EGFR signaling in cancer cells, this growth factor receptor is being targeted clinically with the use of both antibody- and small molecule-based approaches (1). In this issue of the Journal, Lammering et al. (2) extend their previous observations on the usefulness of targeting the EGFR to improve the therapeutic efficacy of ionizing radiation. Previously, these investigators demonstrated that exposure of EGFR-positive human breast cancer cells to therapeutically relevant doses of ionizing radiation in vitro could increase the level of activation of the receptor, which resulted in increased mitogen-activated protein (MAP) kinase signaling (3,4). This phenomenon may underlie the clinical observation of “accelerated repopulation” in which tumor cells undergo stimulated proliferation during a fractionated course of radiation. The authors went on to show that blocking radiation-induced receptor activation could sensitize the cells to the lethal effects of ionizing radiation (5). In the present work, they extend their observations to the in vivo setting and have found that exposure of human breast cancer xenografts to ionizing radiation increased the level of tyrosine-phosphorylated EGFR, a measure of EGFR activation. Furthermore, they showed that blocking receptor activation with the use of an adenoviral vector coding for a dominant-negative EGFR mutant blocked radiation-induced signaling and decreased clonogenic survival of tumor cells in an excision assay. The approach taken by Lammering et al. (2) represents an interesting departure from the classic rationale for use of EGFR as a therapeutic target. In many studies, EGFR has been considered to be a good target because of its likely role in driving some or all of the transformed phenotypes expressed by the cells. On the basis of this reasoning, it has been hypothesized that blockade of EGFR signaling would selectively suppress tumor growth while producing minimal toxicity to normal tissue, which would be anticipated to depend less on EGFR-mediated stimulation. Furthermore, disruption of EGFR signaling could also make tumor cells more vulnerable to more conventional cytotoxic agents, such as chemotherapy or ionizing radiation. By contrast, the report by Lammering et al. (2) focuses on the response of cells that, at baseline, may express normal levels of EGFR and attempts to produce radiosensitization by disrupting a survival response to ionizing radiation. Thus, their demonstration that exposure to radiation can induce receptor activation suggests that signals emanating from the receptor play a role in the survival of cancer cells after radiation. Given the known connection between EGFR activation and signaling pathways that influence cell survival, this is a reasonable hypothesis that their data seem to support. Indeed, the results reported by Lammering et al. (2) may explain, at least in part, the often observed interaction between agents that block receptor signaling and the response to cytotoxic agents (6). As interesting and novel as this approach is to use EGFR as a therapeutic target, it also raises issues that must be considered before the translation of these ideas to the clinical setting. First, it is not yet clear if there is a role for EGFR overexpression in the response to radiation and the sensitization of cancer cells to radiation by EGFR blockade. The MB-MDA-231 cells used in the study by Lammering et al. (2) do not have a genetic alteration involving EGFR, and it is not clear how expression levels of the receptor in these cells compares with levels expressed by proliferating normal epithelial cells that also express EGFR. This issue is relevant to the question of the therapeutic index that may result from this approach. If normal cells expressing physiologic levels of EGFR are sensitized in a manner similar to that seen with the MB-MDA-231 cells, then trying to exploit radiation-induced EGFR activation may also increase normal tissue toxicity. Although the subcutaneous model system chosen for this evaluation by Lammering et al. (2) demonstrates that inhibition of radiation-induced EGFR activation can decrease tumor cell survival, this model does not accurately reflect normal tissue toxicity and, therefore, therapeutic index. By contrast, if cells that overexpress EGFR, either as a primary genetic event or as an epigenetic phenomenon, are sensitized differentially as a result of receptor overexpression, then a therapeutic index is likely to be present that would be important clinically. It would be interesting to determine if there is any relationship between the levels of EGFR expression and the induction of receptor activation by radiation. A second issue raised in the study by Lammering et al. (2) concerns the use of a gene therapy approach to achieve receptor blockade. Despite the fact that the investigators achieved an infection efficiency of approximately 40%, it would seem that there is a need for a bystander effect to affect cells that did not receive the gene. It is not obvious how a bystander effect would be achieved by use of a dominant-negative EGFR construct. Thus, it may be necessary to combine this gene therapy technique with the C225 antibody, which has already produced promising preliminary clinical results in combination with radiation (7) and/or small molecule kinase inhibitors that are currently under investigation, if complete inhibition of EGFR activation is to be achieved. Although issues of therapeutic index and method of target inhibition are still to be resolved, it now seems clear that the combination of molecularly targeted therapy against growth factor receptors with radiation offers an exciting potential advance in cancer treatment. To take full advantage of this potential, it will be crucial to design clinical trials with radiation that permit EGFR activation to be measured, ideally at multiple times during therapy, for at least two reasons. First, the data of Lammering et al. (2) demonstrate that the response of the tumor to radiation (and, potentially, chemotherapy) can affect the molecular target itself. Thus, a single pretreatment biopsy specimen will not reflect the physiologic state of the tumor, even after the first treatment. Second, the stimulation and inhibition of EGFR signaling produce multiple downstream effects in many pathways, and it is not clear which pathways are crucial to the response of tumor tissue or for toxicity in normal tissues. These issues suggest that one goal should be to develop methods of imaging these targets so that they can be assessed noninvasively at multiple times. This combination of a molecular target, a molecular image, and the use of highly conformal radiation therapy that can target these molecular abnormalities offers the potential for a dramatic improvement in the outcome of treatment that, while not yet in our hands, is within our reach. References 1 Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene  2000; 19: 6550–65. Google Scholar 2 Lammering G, Hewit TH, Hawkins WT, Contessa JN, Reardon DB, Lin PS, et al. Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization. J Natl Cancer Inst  2001; 93: 921–9. Google Scholar 3 Schmidt-Ullrich RK, Mikkelsen RB, Dent P, Todd DG, Valerie K, Kavanagh BD, et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene  1997; 15: 1191–7. Google Scholar 4 Carter S, Auer KL, Reardon DB, Birrer M, Fisher PB, Valerie K, et al. Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells. Oncogene  1998; 16: 2787–96. Google Scholar 5 Contessa JN, Reardon DB, Todd D, Dent P, Mikkelsen RB, Valerie K, et al. The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells. Clin Cancer Res  1999; 5: 405–11. Google Scholar 6 Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M, et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene  1999; 18: 2241–51. Google Scholar 7 Bonner JA, Ezekiel MP, Robert F, Meredith RF, Spencer SA, Waksal HW. Continued response following treatment with IMC-C225, an EGFr MoAb combined with RT in advanced head and neck malignancies [abstract]. Proc ASCO  2000; 19: 4a. Google Scholar © Oxford University Press
TI - Epidermal Growth Factor Receptor Signaling and Response of Cancer Cells to Ionizing Radiation
JF - JNCI: Journal of the National Cancer Institute
DO - 10.1093/jnci/93.12.890
DA - 2001-06-20
UR - https://www.deepdyve.com/lp/oxford-university-press/epidermal-growth-factor-receptor-signaling-and-response-of-cancer-7XcytZ6y6d
SP - 890
EP - 891
VL - 93
IS - 12
DP - DeepDyve
ER -