TY - JOUR
T1 - STAT3 Polymorphism Associates With mTOR Inhibitor-Induced Interstitial Lung Disease in Patients With Renal Cell Carcinoma
AU - Yamamoto, Kazuhiro
AU - Ioroi, Takeshi
AU - Shinomiya, Kazuaki
AU - Yoshida, Ayaka
AU - Harada, Kenichi
AU - Fujisawa, Masato
AU - Omura, Tomohiro
AU - Ikemi, Yasuaki
AU - Nakagawa, Shunsaku
AU - Yonezawa, Atsushi
AU - Ogawa, Osamu
AU - Matsubara, Kazuo
AU - Iwamoto, Takuya
AU - Nishikawa, Kohei
AU - Hayashi, Sayaka
AU - Tohara, Daichi
AU - Murakami, Yoji
AU - Motoshima, Takanobu
AU - Jono, Hirofumi
AU - Yano, Ikuko
N1 - Funding Information:
ACKNOWLEDGMENTS: This work was supported in part by JSPS KAKENHI Grant Nos. 16K08401 and 19K07191 and by the Takeda Science Foundation. We thank all of the participating patients, Professor Kohji Takara at Himeji Dokkyo University for providing the human lung-derivative cell lines, and Dr. Masayuki Miyazaki for the arranging and cooperating with the conduct of this study at Nagoya University Hospital. The authors declare no conflicts of interest.
Funding Information:
This work was supported in part by JSPS KAKENHI Grant Nos. 16K08401 and 19K07191 and by the Takeda Science Foundation. We thank all of the participating patients, Professor Kohji Takara at Himeji Dokkyo University for providing the human lung-derivative cell lines, and Dr. Masayuki Miyazaki for the arranging and cooperating with the conduct of this study at Nagoya University Hospital. The authors declare no conflicts of interest.
Publisher Copyright:
Copyright © 2022 Cognizant, LLC.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Epithelial–mesenchymal transition (EMT)
KW - Interstitial lung disease
KW - Polymorphism
KW - STAT3
KW - mTOR inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85129996971&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129996971&partnerID=8YFLogxK
U2 - 10.3727/096504022X16418911579334
DO - 10.3727/096504022X16418911579334
M3 - Article
C2 - 35016744
AN - SCOPUS:85129996971
SN - 0965-0407
VL - 29
SP - 11
EP - 23
JO - Cancer Communications
JF - Cancer Communications
IS - 1
ER -
