Next generation proteomics identifies a potential protein marker of poor response to tyrosine kinase inhibitors in metastatic renal cell carcinoma
| Authors | |
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| Year of publication | 2023 |
| Type | Conference abstract |
| MU Faculty or unit | |
| 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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