TY - JOUR
T1 - Candidate biomarkers for treatment benefit from sunitinib in patients with advanced renal cell carcinoma using mass spectrometry-based (phospho)proteomics
AU - van der Wijngaart, Hanneke
AU - Beekhof, Robin
AU - Knol, Jaco C.
AU - Henneman, Alex A.
AU - de Goeij-de Haas, Richard
AU - Piersma, Sander R.
AU - Pham, Thang V.
AU - Jimenez, Connie R.
AU - Verheul, Henk M. W.
AU - Labots, Mariette
N1 - Funding Information: The authors report no conflict of interest in the relation to the work described. H.M.W.V. has served as a consultant/advisor for Glycostem Inc and Lava Therapeutics for which his institution received a payment. His institution received research funding from Roche and Pfizer. M.L. has served as speaker for BMS and Janssen for which her institution received a payment. Other authors declare that they have no competing interests. Funding Information: This work was supported by a research grant from Vitromics Healthcare Services, The Netherlands to VU University Medical Center, Department of Medical Oncology; no grant number applicable. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
KW - Cancer
KW - Mass spectrometry-based phosphoproteomics
KW - Renal cell carcinoma
KW - Sunitinib
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85175973694&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12014-023-09437-6
DO - https://doi.org/10.1186/s12014-023-09437-6
M3 - Article
C2 - 37940875
SN - 1542-6416
VL - 20
JO - Clinical Proteomics
JF - Clinical Proteomics
IS - 1
M1 - 49
ER -