Phosphoproteomics informed tailored low-dose drug combination strategies in Pancreatic ductal adenocarcinoma cell lines

Pancreatic ductal adenocarcinoma is a devastating disease with poor prognosis, commonly characterized by aberrant signaling. Phosphoproteomics provides a functional scaffold to unravel these complex signaling networks and to identify new targets. By a two-step sequential phospho-peptide enrichment, we generated the phosphoproteome for 9 PDAC cell lines (2 derived from PDX samples). By using integrative inferred kinase activity (INKA) scoring, we identified hyperactive phosphokinases that were subsequently matched to kinase inhibitors. In the absence of an oncogenic driver, low-dose kinase inhibitor combinations against multiple (parallel) activated kinases, provided higher efficacy as compared to single-drug treatment. Tailored low-dose combination strategies exhibited promising efficacy in vitro and in vivo, which may ultimately improve treatment outcomes in PDAC patients.