Priming cells with modulators of cellular signaling ensures enhanced selectivity of HSPG-specific protein-drug conjugate delivery

Protein-drug conjugates (PDCs) constitute rapidly growing group of precise anticancer agents. Receptor-mediated endocytosis is a critical step in PDC action, which ensures delivery of PDC into cancer cell interior. Here we report TriFHS-MMAE, the first multivalent PDC specifically targeting heparan sulphate proteoglycans (HSPGs) overexpressed by pancreatic cancer cells, which induces ultra fast and highly efficient aggregation dependent endocytosis (ADE) of HSPGs. Using high content screening with near kinome-wide library of inhibitors we identified signaling pathways that govern ADE of HSPGs and we discovered cascades that selectively operate in pancreatic cancer versus healthy cells. We show then that priming cells with identified endocytic modulators improves selectivity of the TriFHS-MMAE conjugate. Overall, these findings provide insights into signaling/endocytosis/PDC interplay and for development of specific therapy of pancreatic cancer. These data are raw data from publication by Chorążewska, Ciura et al: Priming cells with modulators of cellular signaling ensures enhanced selectivity of HSPG-specific protein-drug conjugate delivery.