Abstract | BACKGROUND: 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.
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Authors | Hee Sang Hwang, Yun Yong Park, Su Jin Shin, Heounjeong Go, Ja Min Park, Sun Young Yoon, Jae Lyun Lee, Yong Mee Cho |
Journal | Journal of Korean medical science
(J Korean Med Sci)
Vol. 35
Issue 5
Pg. e31
(Feb 10 2020)
ISSN: 1598-6357 [Electronic] Korea (South) |
PMID | 32030920
(Publication Type: Journal Article)
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Copyright | © 2020 The Korean Academy of Medical Sciences. |
Chemical References |
- Biomarkers, Tumor
- Protein Kinase Inhibitors
- Receptors, Tumor Necrosis Factor, Type I
- Tumor Necrosis Factor-alpha
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Topics |
- Adult
- Biomarkers, Tumor
(metabolism)
- Carcinoma, Renal Cell
(diagnosis, metabolism, therapy)
- Drug Resistance, Neoplasm
- Female
- Humans
- Immunohistochemistry
- Kidney Neoplasms
(diagnosis, metabolism, therapy)
- Male
- Middle Aged
- Prognosis
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Receptors, Tumor Necrosis Factor, Type I
(metabolism)
- Signal Transduction
- Survival Analysis
- Treatment Outcome
- Tumor Necrosis Factor-alpha
(metabolism)
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