title: The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.
abstract: Carbon-ion radiotherapy (CIRT) holds promise to treat inoperable locally-advanced non-small cell lung carcinoma (NSCLC), a disease poorly controlled by standard chemoradiotherapy using X-rays. Since CIRT is an extremely limited medical resource, selection of NSCLC patients likely to benefit from it is important; however, biological predictors of response to CIRT are ill-defined. The present study investigated the association between the mutational status of EGFR and KRAS, driver genes frequently mutated in NSCLC, and the relative biological effectiveness (RBE) of carbon-ion beams over X-rays. The assessment of 15 NSCLC lines of different EGFR/KRAS mutational status and that of isogenic NSCLC lines expressing wild-type or mutant EGFR revealed that EGFR-mutant NSCLC cells, but not KRAS-mutant cells, show low RBE. This was attributable to (i) the high X-ray sensitivity of EGFR-mutant cells, since EGFR mutation is associated with a defect in non-homologous end joining, a major pathway for DNA double-strand break (DSB) repair, and (ii) the strong cell-killing effect of carbon-ion beams due to poor repair of carbon-ion beam-induced DSBs regardless of EGFR mutation status. These data highlight the potential of EGFR mutation status as a predictor of response to CIRT, i.e., CIRT may show a high therapeutic index in EGFR mutation-negative NSCLC.
authors.affiliation: 1] Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan [2] Department of Radiology, Chulalongkorn University, Pathumwan, Bangkok, Thailand.
authors.forename: Napapat
authors.initials: N
authors.lastname: Amornwichet
authors.affiliation: 1] Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan [2] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oike
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, Alabama, USA.
authors.forename: Chaitanya S
authors.initials: CS
authors.lastname: Nirodi
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Tottori University Hospital Cancer Center, Yonago, Tottori, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Makino
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hirota
authors.affiliation: Gunma University Heavy Ion Medical Center, Maebashi, Gunma, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Isono
authors.affiliation: Gunma University Heavy Ion Medical Center, Maebashi, Gunma, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Gunma University Heavy Ion Medical Center, Maebashi, Gunma, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ohno
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D063193:Heavy Ion Radiotherapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000532:radiotherapy; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)