Department of Pharmacy, Kobe University HospitalKobeJapan.
Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri UniversityTokushimaJapan.
Oncol Res. 2022 May 4;29(1):11-23. doi: 10.3727/096504022X16418911579334. Epub 2022 Jan 11.
We evaluated the association of signal transducer and activator of transcription 3 () polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the polymorphism, rs4796793 (1697C/G). We evaluated the association of the genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio=11.67, 95% confidential interval=3.0644.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.
我们评估了信号转导和转录激活因子 3（STAT3）多态性与哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂诱导的肾细胞癌（RCC）患者间质性肺病（ILD）发生率的相关性。我们还使用肺源性细胞系来研究这种相关性的机制。对接受 mTOR 抑制剂治疗的转移性 RCC 日本患者进行了 rs4796793（1697C/G）的 多态性分析。我们评估了 基因型与 ILD 发生率和治疗结果的相关性。在主要分析中纳入的 57 例患者中，GG 基因型患者在 140 天内发生 ILD 的比率明显高于其他基因型患者（77.8%比 23.1%，比值比=11.67，95%置信区间=3.0644.46）。GG 基因型患者与其他基因型患者的无进展生存期或治疗失败时间无显著差异。体外研究表明，一些携带 GG 基因型的肺源性细胞系表现出间充质标志物（如纤维连接蛋白、N-钙黏蛋白和波形蛋白）表达增加，上皮标志物 E-钙黏蛋白表达减少，这与暴露于依维莫司有关，尽管 STAT3 表达和活性与基因型无关。总之，rs4796793 多态性的 GG 基因型增加了 mTOR 抑制剂诱导的 ILD 的风险，支持其作为 RCC 的预测标志物。
