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- Title
Candidate biomarkers for treatment benefit from sunitinib in patients with advanced renal cell carcinoma using mass spectrometry-based (phospho)proteomics.
- Authors
van der Wijngaart, Hanneke; Beekhof, Robin; Knol, Jaco C.; Henneman, Alex A.; de Goeij-de Haas, Richard; Piersma, Sander R.; Pham, Thang V.; Jimenez, Connie R.; Verheul, Henk M. W.; Labots, Mariette
- Abstract
The tyrosine kinase inhibitor sunitinib is an effective first-line treatment for patients with advanced renal cell carcinoma (RCC). Hypothesizing that a functional read-out by mass spectrometry-based (phospho, p-)proteomics will identify predictive biomarkers for treatment outcome of sunitinib, tumor tissues of 26 RCC patients were analyzed. Eight patients had primary resistant (RES) and 18 sensitive (SENS) RCC. A 78 phosphosite signature (p < 0.05, fold-change > 2) was identified; 22 p-sites were upregulated in RES (unique in RES: BCAR3, NOP58, EIF4A2, GDI1) and 56 in SENS (35 unique). EIF4A1/EIF4A2 were differentially expressed in RES at the (p-)proteome and, in an independent cohort, transcriptome level. Inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) as determined by INKA was higher in SENS. Posttranslational modifications signature enrichment analysis showed that different p-site-centric signatures were enriched (p < 0.05), of which FGF1 and prolactin pathways in RES and, in SENS, vanadate and thrombin treatment pathways, were most significant. In conclusion, the RCC (phospho)proteome revealed differential p-sites and kinase activities associated with sunitinib resistance and sensitivity. Independent validation is warranted to develop an assay for upfront identification of patients who are intrinsically resistant to sunitinib.
- Subjects
RENAL cell carcinoma; SUNITINIB; THROMBIN receptors; MASS spectrometry; PROTEOMICS; PROTEIN-tyrosine kinase inhibitors; POST-translational modification
- Publication
Clinical Proteomics, 2023, Vol 20, Issue 1, p1
- ISSN
1542-6416
- Publication type
Article
- DOI
10.1186/s12014-023-09437-6