Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma

Autor: Jae-Lyun Lee, Su Jin Shin, Yun Yong Park, Heoun Jeong Go, Hee Sang Hwang, Yong Mee Cho, Sun Young Yoon, Ja Min Park
Rok vydání: 2020
Předmět:
Adult
Male
Tyrosine Kinase Inhibitor
Microarray
medicine.drug_class
Drug Resistance
Drug resistance
Tyrosine-kinase inhibitor
Clear Cell Renal Cell Carcinoma
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Biomarkers
Tumor
medicine
Humans
Oncology & Hematology
030212 general & internal medicine
Carcinoma
Renal Cell
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
business.industry
General Medicine
Middle Aged
Prognosis
medicine.disease
Immunohistochemistry
Survival Analysis
Kidney Neoplasms
TNF-α Pathway
respiratory tract diseases
TNFR1
Gene expression profiling
Clear cell renal cell carcinoma
Treatment Outcome
Drug Resistance
Neoplasm
Receptors
Tumor Necrosis Factor
Type I
Cancer research
Original Article
Female
Tumor necrosis factor alpha
business
Signal Transduction
Zdroj: Journal of Korean Medical Science
ISSN: 1598-6357
1011-8934
DOI: 10.3346/jkms.2020.35.e31
Popis: Background Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. Methods We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. Results TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. Conclusion TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.
Graphical Abstract
Databáze: OpenAIRE
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