Biology contribution
Enhancement of radiosensitivity by dual inhibition of the HER family with ZD1839 (“Iressa”) and trastuzumab (“Herceptin”)

https://doi.org/10.1016/j.ijrobp.2006.05.036Get rights and content

Purpose: The aims of this study were twofold: (1) to examine the effects of dual inhibition of 2 members of the HER family, the epidermoid growth factor receptor (EGFR) and HER2/neu, by gefitinib (ZD1839) and trastuzumab on radiosensitivity; and (2) to explore the molecular mechanism of radiosensitization especially focusing on the survival signal transduction pathways by using A431 human vulvar squamous carcinoma cells expressing EGFR and HER2/neu.

Methods and Materials: The effects of inhibitors on the radiation-induced activation of EGFR and/or HER2/neu, and the intracellular proteins that are involved in their downstream signaling, were quantified by the Western blot. Radiosensitizing effects by the blockage of EGFR and/or HER2/neu were determined by a clonogenic assay.

Results: Radiation-induced activation of the EGFR and HER2/neu was inhibited with ZD1839 and/or trastuzumab. ZD1839 also inhibited the radiation-induced phosphorylation of HER2/neu. Radiation in combination with the HER family inhibitors inhibited the activation of Akt and MEK1/2, the downstream survival signaling of the HER family. ZD1839 enhanced radiosensitivity with a dose-modifying factor (DMF) (SF3) of 1.45 and trastuzumab did so with a DMF (SF3) of 1.11. Simultaneous blockade of EGFR and HER2/neu induced a synergistic radiosensitizing effect with a DMF (SF3) of 2.29.

Conclusions: The present data suggest that a dual EGFR and HER2/neu targeting may have potential for radiosensitization in tumors in which both of these pathways are active.

Keywords

Radiosensitization
HER family
Dual inhibition
ZD1839
Trastuzumab

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Supported in part by Grants-Aid for Scientific Research on Priority Areas (Nos. 121217022 and No. 17016073) and for Scientific Research (No. 16591229) from the Ministry of Education, Science and Culture of Japan, and Grants-Aid from Takeda Science Foundation, Osaka, Japan.

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