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- Title
Kinase Inhibitor Treatment of Patients with Advanced Cancer Results in High Tumor Drug Concentrations and in Specific Alterations of the Tumor Phosphoproteome.
- Authors
Labots, Mariette; Pham, Thang V.; Honeywell, Richard J.; Knol, Jaco C.; Beekhof, Robin; de Goeij-de Haas, Richard; Dekker, Henk; Neerincx, Maarten; Piersma, Sander R.; van der Mijn, Johannes C.; van der Peet, Donald L.; Meijerink, Martijn R.; Peters, Godefridus J.; van Grieken, Nicole C.T.; Jiménez, Connie R.; Verheul, Henk M.W.
- Abstract
Identification of predictive biomarkers for targeted therapies requires information on drug exposure at the target site as well as its effect on the signaling context of a tumor. To obtain more insight in the clinical mechanism of action of protein kinase inhibitors (PKIs), we studied tumor drug concentrations of protein kinase inhibitors (PKIs) and their effect on the tyrosine-(pTyr)-phosphoproteome in patients with advanced cancer. Tumor biopsies were obtained from 31 patients with advanced cancer before and after 2 weeks of treatment with sorafenib (SOR), erlotinib (ERL), dasatinib (DAS), vemurafenib (VEM), sunitinib (SUN) or everolimus (EVE). Tumor concentrations were determined by LC-MS/MS. pTyr-phosphoproteomics was performed by pTyr-immunoprecipitation followed by LC-MS/MS. Median tumor concentrations were 2–10 µM for SOR, ERL, DAS, SUN, EVE and >1 mM for VEM. These were 2–178 × higher than median plasma concentrations. Unsupervised hierarchical clustering of pTyr-phosphopeptide intensities revealed patient-specific clustering of pre- and on-treatment profiles. Drug-specific alterations of peptide phosphorylation was demonstrated by marginal overlap of robustly up- and downregulated phosphopeptides. These findings demonstrate that tumor drug concentrations are higher than anticipated and result in drug specific alterations of the phosphoproteome. Further development of phosphoproteomics-based personalized medicine is warranted.
- Subjects
BIOPSY; CANCER patients; DRUG monitoring; LIQUID chromatography; MASS spectrometry; PHOSPHOPROTEINS; TUMORS; TYROSINE; PROTEOMICS; TREATMENT effectiveness; PROTEIN kinase inhibitors; PRECIPITIN tests; DASATINIB; ERLOTINIB; EVEROLIMUS; SORAFENIB; PHARMACODYNAMICS
- Publication
Cancers, 2020, Vol 12, Issue 2, p330
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers12020330