Next generation proteomics identifies a potential protein marker of poor response to tyrosine kinase inhibitors in metastatic renal cell carcinoma

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Authors

BOUCHALOVÁ Pavla ŠIMONÍK Jan LAPČÍK Petr JANÁČOVÁ Lucia POTĚŠIL David PODHOREC Ján HLOBILKOVÁ Alice POPOVICI Vlad HORA Milan POPRACH Alexandr FIALA Ondřej BOUCHAL Pavel

Year of publication 2023
Type Conference abstract
MU Faculty or unit

Faculty of Science

Citation
Description 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.
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