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@proceedings{2341817,
author = {Bouchalová, Pavla and Šimoník, Jan and Lapčík, Petr and Janáčová, Lucia and Potěšil, David and Podhorec, Ján and Hlobilková, Alice and Popovici, Vlad and Hora, Milan and Poprach, Alexandr and Fiala, Ondřej and Bouchal, Pavel},
booktitle = {Abstract Book of EACR Conference: Cellular Bases for Patient Response to Cancer Therapies, Lyon, Francie 14.-16.11.2023, P12},
keywords = {proteomics; metastatic renal cell cancer; tyrosine kinase inhibitors; therapy response; biomarker},
language = {eng},
title = {Next generation proteomics identifies a potential protein marker of poor response to tyrosine kinase inhibitors in metastatic renal cell carcinoma},
url = {https://www.eacr.org/conference/cellularbases2023/digital-abstracts/detail/5668},
year = {2023}
}
TY - CONF
ID - 2341817
AU - Bouchalová, Pavla - Šimoník, Jan - Lapčík, Petr - Janáčová, Lucia - Potěšil, David - Podhorec, Ján - Hlobilková, Alice - Popovici, Vlad - Hora, Milan - Poprach, Alexandr - Fiala, Ondřej - Bouchal, Pavel
PY - 2023
TI - Next generation proteomics identifies a potential protein marker of poor response to tyrosine kinase inhibitors in metastatic renal cell carcinoma
KW - proteomics
KW - metastatic renal cell cancer
KW - tyrosine kinase inhibitors
KW - therapy response
KW - biomarker
UR - https://www.eacr.org/conference/cellularbases2023/digital-abstracts/detail/5668
N2 - Metastatic renal cell carcinoma (mRCC) is a serious disease which represents one quarter of newly diagnosed RCC patients. A targeted therapy with tyrosine kinase inhibitors (TKI) has been used in first line treatment of mRCC patients with good or intermediate prognosis for years. However, approximately a half of mRCC patients do not profit from this therapy, and there is no clinical marker identifying non-responders. To address this clinical issue, we performed retrospective proteomics study on 53 mRCC tumors treated with sunitinib and pazopanib (including 23/30 responders/non-responders) using next-generation LC-DIA-MS/MS with consistent quantification of 5977 protein groups (FDR 0.01). Analysis of differential protein abundance identified 12 proteins associated with treatment response, of which 5 were successfully validated in an independent cohort of 22 mRCC tumors (10/12 responders/non-responders). Of these, transmembrane glycoprotein GPNMB exhibited the best profile and was connected to best treatment response. The trend of increased GPNMB levels was also observed in independent cohort of mRCC tissues (n=40) using immunohistochemistry. To functionally confirm GPNMB role in metastatic potential of tumor cells, we knocked-out its expression using CRISPR/Cas9 in 786-0 RCC cells. Comparison of parental and GPNMB-/- cells confirmed that GPNMB significantly supported migration capacity and invasiveness of 786-0 cells. Pathway analysis indicates association of GPNMB deregulation with enrichment of INFLAMMATORY_RESPONSE and thus modulation of immune response in mRCC tissues and 786-0 cells. Our data shows that GPNMB has a potential to serve as a biomarker of poor mRCC response to TKI treatment. Importantly, as GPNMB supports metastatic potential of tumor cells, the data indicate that transmembrane GPNMB could serve as a therapeutic target in mRCC alternatively to rTKI treatment.
ER -
BOUCHALOVÁ, Pavla, Jan ŠIMONÍK, Petr LAPČÍK, Lucia JANÁČOVÁ, David POTĚŠIL, Ján PODHOREC, Alice HLOBILKOVÁ, Vlad POPOVICI, Milan HORA, Alexandr POPRACH, Ondřej FIALA a Pavel BOUCHAL. Next generation proteomics identifies a potential protein marker of poor response to tyrosine kinase inhibitors in metastatic renal cell carcinoma. In \textit{Abstract Book of EACR Conference: Cellular Bases for Patient Response to Cancer Therapies, Lyon, Francie 14.-16.11.2023, P12}. 2023.
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