J Korean Med Sci.  2020 Feb;35(5):e31. 10.3346/jkms.2020.35.e31.

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

Affiliations
  • 1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. yongcho@amc.seoul.kr
  • 2Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
  • 3Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 4Department of Pathology, Hanyang University College of Medicine, Seoul, Korea.
  • 5Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Abstract

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.

Keyword

Clear Cell Renal Cell Carcinoma; Tyrosine Kinase Inhibitor; Drug Resistance; TNFR1; TNF-α Pathway

MeSH Terms

Biomarkers
Carcinoma, Renal Cell*
Cohort Studies
Dataset
Drug Resistance
Gene Expression
Gene Expression Profiling
Heterografts
Humans
Immunohistochemistry
Protein-Tyrosine Kinases
Receptors, Tumor Necrosis Factor
Receptors, Tumor Necrosis Factor, Type I*
Tumor Necrosis Factor-alpha
Biomarkers
Protein-Tyrosine Kinases
Receptors, Tumor Necrosis Factor
Receptors, Tumor Necrosis Factor, Type I
Tumor Necrosis Factor-alpha
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