分子標的型抗がん薬による間質性肺疾患発症の分子機構に基づく予測法の開発—mTOR阻害薬による間質性肺疾患とSTAT3の関連—

Interstitial lung disease (ILD) is a serious adverse event common to many molecular targeted anticancer drugs. The development of ILD significantly reduces the QOL of patients and results in treatment discontinuation. Because the development of ILD is also associated with therapeutic efficacy, the establishment of prediction strategies for ILD is important. We have focused on signal transducer and activator of transcription 3 (STAT3) as an important mechanistic factor in ILD induced by molecular targeted drugs. Our study aimed to establish mechanism-based ILD prediction strategies; therefore, we investigated the hypothesis that a genetic polymorphism in STAT3 is a predictive factor of the incidence of ILD induced by mammalian target of rapamycin (mTOR) inhibitors, a class of molecular targeted drugs associated with a higher incidence of ILD. Our clinical study clearly demonstrated that the rate of ILD induced by mTOR inhibitors was significantly higher in patients with the G allele homozygous genotype of STAT3 -1697C>G compared with those with other genotypes. The cumulative incidence of ILD in patients with the G allele homozygous genotype was significantly higher compared with that in patients carrying other genotypes. Furthermore, our in vitro study indicated that the epithelial-to-mesenchymal transition (EMT), a pre-process of tissue fibrosis, was induced by an mTOR inhibitor in lung alveolar epithelial cell lines carrying the G allele homozygous genotype which was associated with a higher risk of ILD. Our study provided a novel predictive strategy for the development of ILD induced by molecular targeted drugs.