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

111 Citations (Scopus)

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

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Mutation
DNA-Activated Protein Kinase
Radiation
Ionizing Radiation
Cell Line
Catalytic Domain
Double-Stranded DNA Breaks
Radiation Tolerance
Cell Survival
Epithelial Cells
Survival
DNA
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Somatic mutations in the tyrosine kinase domain of Epidermal Growth Factor Receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. / Das, Amit K.; Chen, Benjamin P.; Story, Michael D.; Sato, Mitsuo; Minna, John D.; Chen, David J.; Nirodi, Chaitanya S.

In: Cancer Research, Vol. 67, No. 11, 01.06.2007, p. 5267-5274.

Research output: Contribution to journalArticle

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