STAT3 polymorphism associates with mTOR inhibitor-induced interstitial lung disease in patients with renal cell carcinoma

We evaluated the association of signal transducer and activator of transcription 3(STAT3) 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 mTORinhibitors were genotyped for the STAT3 polymorphism, rs4796793. We evaluated the association of the STAT3 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 CC genotype compared with those with other genotypes (77.8% versus 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06–44.46). Meanwhile, there were no significant differences in progression-free survival ortime-to-treatment failure between the patients with the CC genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the CC 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 CCgenotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitorinduced ILD, supporting its use as a predictive marker for RCC.