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doi: 10.1038/srep11305.

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

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

Napapat Amornwichet et al. Sci Rep. .

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.

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Figures

Figure 1
Figure 1. Sensitivity of EGFR-mutant, KRAS-mutant, or EGFR/KRAS wild-type NSCLC lines to X-rays or carbon-ion beams assessed by clonogenic survival assay.
C-ion, carbon-ion; mut, mutant; wt, wild-type. The original survival curves are shown in Supplementary Figure 1. (a) D10 for X-rays and carbon-ion beams. (b) RBE of carbon-ion beams at D10. (c) Statistical analysis of the difference in D10 for X-rays or carbon-ion beams, or RBE of carbon-ion beams in NSCLC lines based on EGFR or KRAS mutation status. P values on the significant differences in the mean values (black lines) between mutant and wild-type lines were shown.
Figure 2
Figure 2. Sensitivity of isogenic A549 cells stably expressing wild-type or mutant (ΔE746-A750 or L858R) EGFR proteins to X-rays or carbon-ion beams assessed by clonogenic survival assay.
Data are represented as mean ± standard deviations. C-ion, carbon-ion; wt, wild-type.
Figure 3
Figure 3. Repair of X-ray- or carbon-ion beam-induced DSBs in EGFR-mutant or wild-type NSCLC lines assessed by immunofluorescence staining of γH2AX.
Cells were exposed to X-rays (6 Gy) or carbon-ion beams (2 Gy) in the presence or absence of the DNA-PKcs inhibitor NU7441 (10 μM) and stained with an antibody to γH2AX 24 h post-irradiation. The number of γH2AX foci per nucleus was scored in 30-50 cells for each experimental condition using a fluorescence microscope at ×ばつ100 magnification. The results of a representative experiment are shown as box plots. (a) X-rays. (b) Carbon-ion beams (C-ion).

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