Somatic mutations in the tyrosine kinase domain of Epidermal Growth Factor Receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma

Amit K. Das, Benjamin P. Chen, Michael D. Story, Mitsuo Sato, John D. Minna, David J. Chen, Chaitanya S. Nirodi

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

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 ΔE746-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 ΔE746-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.

Original languageEnglish (US)
Pages (from-to)5267-5274
Number of pages8
JournalCancer research
Volume67
Issue number11
DOIs
StatePublished - Jun 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Somatic mutations in the tyrosine kinase domain of Epidermal Growth Factor Receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma'. Together they form a unique fingerprint.

  • Cite this