Open Access

ARTICLE

STAT3 Polymorphism Associates With mTOR Inhibitor-Induced Interstitial Lung Disease in Patients With Renal Cell Carcinoma

Kazuhiro Yamamoto^*, Takeshi Ioroi^*, Kazuaki Shinomiya^†, Ayaka Yoshida^*, Kenichi Harada^‡, Masato Fujisawa^‡, Tomohiro Omura^*, Yasuaki Ikemi^§, Shunsaku Nakagawa^§, Atsushi Yonezawa^§, Osamu Ogawa^¶, Kazuo Matsubara^§, Takuya Iwamoto^#, Kohei Nishikawa^**, Sayaka Hayashi^††, Daichi Tohara^††, Yoji Murakami^‡‡, Takanobu Motoshima^‡‡, Hirofumi Jono^††, Ikuko Yano^*§

* Department of Pharmacy, Kobe University Hospital, Kobe, Japan
† Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
‡ Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
§ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
¶ Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
# Department of Pharmacy, Mie University Hospital, Mie, Japan
** Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie, Japan
†† Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan
‡‡ Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

Oncology Research 2021, 29(1), 11-23. https://doi.org/10.3727/096504022X16418911579334

Abstract

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% vs. 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06–44.46). 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 STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

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