Open AccessSTAT3 Polymorphism Associates With mTOR Inhibitor-Induced Interstitial Lung Disease in Patients With Renal Cell Carcinoma
Author(s) -
Kazuhiro Yamamoto,
Takeshi Ioroi,
Kazuaki Shinomiya,
Ayaka Yoshida,
Kenichi Harada,
Masato Fujisawa,
Tomohiro Omura,
Yukio Ikemi,
Shoichi Nakagawa,
Atsushi Yonezawa,
Osamu Ogawa,
Kazuo Matsubara,
Takeshi Iwamoto,
Kohei Nishikawa,
Saihou Hayashi,
Daichi Tohara,
Yoji Murakami,
Takanobu Motoshima,
Hirofumi Jono,
Ikuko Yano
Publication year - 2022
Publication title -
oncology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 57
eISSN - 1555-3906
pISSN - 0965-0407
DOI - 10.3727/096504022x16418911579334
Subject(s) - genotype , everolimus , renal cell carcinoma , interstitial lung disease , lung cancer , medicine , odds ratio , cancer research , pathology , oncology , biology , lung , gastroenterology , genetics , gene
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 mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (-1697C/G). 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 GG 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 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 STAT3 -1697C/G polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.