@article{150057cf3b09490da6511b45c9cabd65,
title = "Phosphoproteomics guides effective low-dose drug combinations against pancreatic ductal adenocarcinoma",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited set of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a readout of aberrant signaling and has the potential to identify new targets and guide treatment decisions. Using two-step sequential phosphopeptide enrichment, we generate a comprehensive phosphoproteome and proteome of nine PDAC cell lines, encompassing more than 20,000 phosphosites on 5,763 phospho-proteins, including 316 protein kinases. By using integrative inferred kinase activity (INKA) scoring, we identify multiple (parallel) activated kinases that are subsequently matched to kinase inhibitors. Compared with high-dose single-drug treatments, INKA-tailored low-dose 3-drug combinations against multiple targets demonstrate superior efficacy against PDAC cell lines, organoid cultures, and patient-derived xenografts. Overall, this approach is particularly more effective against the aggressive mesenchymal PDAC model compared with the epithelial model in both preclinical settings and may contribute to improved treatment outcomes in PDAC patients.",
keywords = "CP: Cancer, IMAC, drug combinations, kinase activity, kinases, pTyr IP, pancreatic ductal adenocarcinoma, personalized medicine, pharmacology, phosphoproteomics",
author = "Andrea Vall{\'e}s-Mart{\'i} and Giulia Mantini and Paul Manoukian and Cynthia Waasdorp and Sarasqueta, {Arantza Fari{\~n}a} and {de Goeij-de Haas}, {Richard R.} and Henneman, {Alex A.} and Piersma, {Sander R.} and Pham, {Thang V.} and Knol, {Jaco C.} and Elisa Giovannetti and Bijlsma, {Maarten F.} and Jim{\'e}nez, {Connie R.}",
note = "Funding Information: This project was supported by the Dutch Cancer Society (KWF Kankerbestrijding, grant KWF2016-1/10212 to C.R.J., M.F.B., and E.G.), funding to M.F.B. and P.M. from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Program under Marie Sk{\l}odowska-Curie grant agreement 861196 designated PRECODE, and funding to E.G. from the Associazione Italiana per la Ricerca sul Cancro (AIRC, grant IG-24444). Cancer Center Amsterdam and Netherlands Organisation for Scientific Research ( NWO -Middelgroot project 91116017 ) are acknowledged for support of the mass spectrometry infrastructure and Surfsara for computing infrastructure (reference e-infra 180166 ). Funding Information: M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma. He has acted as a consultant to Servier and Olympus. None of these companies was involved in the design of the study or the drafting of this manuscript. Funding Information: This project was supported by the Dutch Cancer Society (KWF Kankerbestrijding, grant KWF2016-1/10212 to C.R.J. M.F.B. and E.G.), funding to M.F.B. and P.M. from the European Union's Horizon 2020 Research and Innovation Program under Marie Sk{\l}odowska-Curie grant agreement 861196 designated PRECODE, and funding to E.G. from the Associazione Italiana per la Ricerca sul Cancro (AIRC, grant IG-24444). Cancer Center Amsterdam and Netherlands Organisation for Scientific Research (NWO-Middelgroot project 91116017) are acknowledged for support of the mass spectrometry infrastructure and Surfsara for computing infrastructure (reference e-infra180166). A.V.M. designed and performed experiments, analyzed data, performed bioinformatic analyses, and wrote the manuscript. R.R.d.G.-d.H. performed the phosphoproteomic sample processing. S.R.P. performed the mass spectrometry measurements and analyzed data. G.M. T.V.P. S.R.P. J.C.K. A.A.H. and A.V.M. performed bioinformatic analyses. P.M. contributed to organoid experiments. C.W. and A.V.M. performed in vivo experiments. A.F.S. performed the pathology assessment. M.F.B. C.R.J. and E.G. designed and supervised the study and wrote the manuscript. M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma. He has acted as a consultant to Servier and Olympus. None of these companies was involved in the design of the study or the drafting of this manuscript. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = jun,
day = "27",
doi = "https://doi.org/10.1016/j.celrep.2023.112581",
language = "English",
volume = "42",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}