2023
Transmembrane glycoprotein GPNMB is a potential marker of poor response of metastatic renal cell carcinoma to tyrosine kinase receptor inhibitor treatment
ŠIMONÍK, Jan, Pavla BOUCHALOVÁ, Petr LAPČÍK, David POTĚŠIL, Ján PODHOREC et. al.Základní údaje
Originální název
Transmembrane glycoprotein GPNMB is a potential marker of poor response of metastatic renal cell carcinoma to tyrosine kinase receptor inhibitor treatment
Autoři
ŠIMONÍK, Jan (203 Česká republika, domácí), Pavla BOUCHALOVÁ (203 Česká republika, domácí), Petr LAPČÍK (203 Česká republika, domácí), David POTĚŠIL (203 Česká republika, domácí), Ján PODHOREC (703 Slovensko, domácí), Lucia JANÁČOVÁ (703 Slovensko, domácí), Alice HLOBILKOVÁ (203 Česká republika, domácí), Vlad POPOVICI (642 Rumunsko, domácí), Alexandr POPRACH (203 Česká republika, domácí), Milan HORA (203 Česká republika, domácí), Ondřej FIALA (203 Česká republika) a Pavel BOUCHAL (203 Česká republika, domácí)
Vydání
9th Informal Proteomic Meeting November 30 – December 1, Mělník, Masaryk Cultural House, 2023
Další údaje
Jazyk
angličtina
Typ výsledku
Konferenční abstrakt
Obor
10608 Biochemistry and molecular biology
Stát vydavatele
Česká republika
Utajení
není předmětem státního či obchodního tajemství
Kód RIV
RIV/00216224:14310/23:00132430
Organizační jednotka
Přírodovědecká fakulta
Klíčová slova anglicky
Transmembrane glycoprotein GPNMB; metastatic renal cell carcinoma; tyrosine kinase receptor inhibitor treatment
Změněno: 5. 4. 2024 09:58, Mgr. Tereza Miškechová
Anotace
V originále
Metastatic renal cell carcinoma (mRCC) represents a systemic disease with a very poor prognosis. A targeted therapy with receptor tyrosine kinase inhibitors (rTKI) has been used in the first-line treatment of mRCC patients with good or intermediate prognosis for many years. However, about half of the patients respond poorly or do not respond to this treatment, and there is no clinical marker identifying these non-responders. To understand the molecular mechanisms associated with a poor response to rTKI and to identify patients who would benefit from an alternate treatment (e.g. immunotherapy or clinical trial), we performed a retrospective proteomics study on 53 mRCC tumors treated with rTKI (23 responders/30 non-responders) using next-generation, data-independent acquisition (DIA) mass spectrometry with a consistent quantification of 5977 protein groups (FDR 0.01). Analysis of differential protein abundance identified a panel of 12 proteins associated with treatment response, of which 5 were successfully validated in an independent cohort of 22 mRCC tumors (10 responders /12 non-responders). Of these, transmembrane glycoprotein GPNMB exhibited the best predictive value (AUC.5=0.756, p=4.733.10 -10 ), was associated with the time to response (p=0.048), and the trend of increased GPNMB protein levels was visible in another independent cohort (n=40) using immunohistochemistry. To investigate the potential of GPNMB to serve as an alternative therapeutic target in mRCC, we knocked out its expression using CRISPR/Cas9 in 786-0 cell line derived from RCC. Comparison of parental and GPNMB -/- cells showed that higher GPNMB protein level supports migration capacity of RCC cells in the scratch assay (p=0.0073) and Transwell assay (p < 0.0001), and supports cell invasiveness in Transwell assay (p=0.0009) and 3D invasion assay (p < 0.0001). In summary, GPNMB has the potential to serve as a biomarker of a poor mRCC response to rTKI treatment and potentially also as a therapeutic target in mRCC non-responding to rTKI as an alternative to TKI and potentially immunotherapy treatment.
Návaznosti
| LM2018129, projekt VaV |
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| LM2023042, projekt VaV |
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| LX22NPO5102, projekt VaV |
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| MUNI/A/1313/2022, interní kód MU |
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| NV19-08-00250, projekt VaV |
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