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.
Highlights
Ten facilities in the world; this situation may not be substantially improved in the few decades because of high costs
Little is known about the association between driver gene mutation status and relative biological effectiveness (RBE) of carbon-ion beams in non-small cell lung carcinoma (NSCLC)
These data indicate that carbon-ion beams have a higher cell-killing effect than X-rays regardless of EGFR mutation status
Summary
We first examined the sensitivity of 15 NSCLC lines with different EGFR and KRAS mutational statuses to X-rays or carbon-ion beams by clonogenic survival assay (Fig. 1a, Supplementary Fig. 1). When the cells were irradiated with X-rays or carbon-ion beams for the same dose of 2 Gy, the number of γ H2AX foci was significantly smaller in X-rays than in carbon-ion beams, in all the EGFR-mutant and the EGFR wild-type cells examined (Supplementary Fig. 2) Taken together, these data indicate that the repair efficacy for carbon-ion beam-induced DSBs is lower than that of X-ray-induced DSBs regardless of the EGFR mutation status. Studies assessing the association between the mutation status of a wide panel of cancer-related genes and the sensitivity of cancer cells to X-rays and carbon-ion beams will further elucidate genetic profiles that affect radiosensitivity and RBE, and will provide biological basis for the establishment of useful predictors for personalized radiotherapy To this end, the mutational analysis of 409 known cancer-related genes in the 15 NSCLC lines used in the present study is ongoing. EGFR mutation-negative NSCLCs show a high RBE compared to EGFR-mutant NSCLCs and may, benefit from CIRT
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