Details

Autor(en) / Beteiligte

• 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

Titel

Kinase Inhibitor Treatment of Patients with Advanced Cancer Results in High Tumor Drug Concentrations and in Specific Alterations of the Tumor Phosphoproteome

Ist Teil von

• Cancers, 2020-02, Vol.12 (2), p.330

Ort / Verlag

Switzerland: MDPI

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.