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Somatic Mutations in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor (EGFR) Abrogate EGFR-Mediated Radioprotection in Non–Small Cell Lung Carcinoma

Departments of ¹ Radiation Oncology, ² Internal Medicine, ³ Pathology, and ⁴ Pharmacology and ⁵ Hamon Cancer Center for Therapeutic Oncology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Chaitanya S. Nirodi, Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC 7.208, Mail Code 9187, Dallas, TX 75390. Phone: 214-648-7318; Fax: 214-648-5995; E-mail: chaitanya.nirodi{at}utsouthwestern.edu.

The epidermal growth factor receptor (EGFR) is an important determinant of radioresponse, whose elevated expression and activity frequently correlates with radioresistance in several cancers, including non–small cell lung carcinoma (NSCLC). We reported recently that NSCLC cell lines harboring somatic, activating mutations in the tyrosine kinase domain (TKD) of the EGFR exhibit significant delays in the repair of DNA double-strand breaks (DSB) and poor clonogenic survival in response to radiation. Here, we explore the mechanisms underlying mutant EGFR-associated radiosensitivity. In three representative NSCLC cell lines, we show that, unlike wild-type (WT) EGFR, receptors with common oncogenic TKD mutations, L858R or E746-E750, are defective in radiation-induced translocation to the nucleus and fail to bind the catalytic and regulatory subunits of the DNA-dependent protein kinase (DNA-PK), a key enzyme in the nonhomologous end-joining repair pathway. Moreover, despite the presence of WT EGFR, stable exogenous expression of either the L858R or the E746-E750 mutant forms of EGFR in human bronchial epithelial cells significantly delays repair of ionizing radiation (IR)–induced DSBs, blocks the resolution of frank or microhomologous DNA ends, and abrogates IR-induced nuclear EGFR translocation or binding to DNA-PK catalytic subunit. Our study has identified a subset of naturally occurring EGFR mutations that lack a critical radioprotective function of EGFR, providing valuable insights on how the EGFR mediates cell survival in response to radiation in NSCLC cell lines. [Cancer Res 2007;67(11):5267–74]

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				D. J. Chen and C. S. Nirodi The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage Clin. Cancer Res., November 15, 2007; 13(22): 6555 - 6560. [Abstract] [Full Text] [PDF]