title: Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation.
abstract: Non-small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor-acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500- to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the DeltaE746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance.
authors.affiliation: 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, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Das
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.forename: Robert
authors.initials: R
authors.lastname: Graves
authors.forename: Stella
authors.initials: S
authors.lastname: Redpath
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Chaitanya S
authors.initials: CS
authors.lastname: Nirodi
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001610:Beta Particles; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000737:chemistry / Q000502:physiology*; D005091:Exons / Q000235:genetics; D005720:Gamma Rays; D000077156:Gefitinib; D018773:Genes, erbB-1; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
chemical_list: D009363:Neoplasm Proteins; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib