IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma

• Published in: Investigative and clinical urology Vol. 65; no. 1; pp. 84 - 93
• Main Authors: Jeong, Se Un, Park, Ja-Min, Yoon, Sun Young, Hwang, Hee Sang, Go, Heounjeong, Shin, Dong-Myung, Ju, Hyein, Sung, Chang Ohk, Lee, Jae-Lyun, Jeong, Gowun, Cho, Yong Mee
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Urological Association 01.01.2024; Korean Urological Association; 대한비뇨의학회
• Subjects: carcinoma renal cell; Carcinoma, Renal Cell - drug therapy; drug resistance; Drug Resistance, Neoplasm; Humans; ifitm3 protein human; Membrane Proteins - genetics; mitogen-activated protein kinase 1; Original; RNA-Binding Proteins - genetics; Sunitinib - pharmacology; TNF Receptor-Associated Factor 6; Transcription Factor AP-1; Tyrosine Kinase Inhibitors - pharmacology; Vascular Endothelial Growth Factor A; 비뇨기과학; Mitogen-activated protein kinase 1; TNF receptor-associated factor 6; IFITM3 protein, human; Drug resistance; Carcinoma, renal cell
• ISSN: 2466-0493; 2466-054X; 2466-054X
• DOI: 10.4111/icu.20230294

Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through and studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.