The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells

• DOI: 10.1038/srep11305
• Publication Date: 2015-06-11T14:12:41Z
• Authors: Napapat Amornwichet; Takahiro Oike; Atsushi Shibata; Chaitanya S. Nirodi; Hideaki Ogiwara; Haruhiko Makino; Yuka Kimura; Yuka Hirota; Mayu Isono; Yukari Yoshida; Tatsuya Ohno; Takashi Kohno; Takashi Nakano
• Keywords: Lung Neoplasms; DNA Repair; Heavy Ion Radiotherapy; Article; 3. Good health; ErbB Receptors; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; 0302 clinical medicine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Mutation; Humans; DNA Breaks, Double-Stranded

AbstractCarbon-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.