Phosphoproteomics guides effective low-dose drug combinations against pancreatic ductal adenocarcinoma
Andrea Vallés-Martí,
Giulia Mantini,
Paul Manoukian,
Cynthia Waasdorp,
Arantza Fariña Sarasqueta,
Richard R. de Goeij-de Haas,
Alex A. Henneman,
Sander R. Piersma,
Thang V. Pham,
Jaco C. Knol,
Elisa Giovannetti,
Maarten F. Bijlsma,
Connie R. Jiménez
Affiliations
Andrea Vallés-Martí
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Pharmacology Laboratory, Amsterdam, the Netherlands
Giulia Mantini
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands; Cancer Center Amsterdam, Pharmacology Laboratory, Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme, Pisa, Italy
Paul Manoukian
Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, the Netherlands
Cynthia Waasdorp
Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, the Netherlands
Arantza Fariña Sarasqueta
Amsterdam University Medical Center, Pathology Department, Amsterdam, the Netherlands
Richard R. de Goeij-de Haas
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands
Alex A. Henneman
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands
Sander R. Piersma
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands
Thang V. Pham
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands
Jaco C. Knol
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands
Elisa Giovannetti
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Pharmacology Laboratory, Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme, Pisa, Italy
Maarten F. Bijlsma
Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, the Netherlands
Connie R. Jiménez
Amsterdam University Medical Center, VU University, Department of Medical Oncology, Amsterdam, the Netherlands; Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, the Netherlands; Corresponding author
Summary: 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.
