Systems Pharmacodynamic Model of Combined Gemcitabine and Trabectedin in Pancreatic Cancer Cells. Part II: Cell Cycle, DNA Damage Response, and Apoptosis Pathways.

ABSTRACT

Despite decades of research efforts, pancreatic adenocarcinoma (PDAC) continues to present a formidable clinical challenge, demanding innovative therapeutic approaches. In a prior study, we reported the synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells. To investigate potential mechanisms underlying this synergistic pharmacodynamic interaction, liquid chromatography-mass spectrometry-based proteomic analysis was performed, and a systems pharmacodynamics model (SPD) was developed to capture pancreatic cancer cell responses to gemcitabine and trabectedin, alone and combined, at the proteome level. Companion report Part I describes the proteomic workflow and drug effects on the upstream portion of the SPD model related to cell growth and migration, specifically the RTK-, integrin-, GPCR-, and calcium-signaling pathways. This report presents Part II of the SPD model. Here we describe drug effects on pathways associated with cell cycle, DNA damage response (DDR), and apoptosis, and provide insights into underlying mechanisms. Drug combination effects on protein changes in the cell cycle- and apoptosis pathways contribute to the synergistic effects observed between gemcitabine and trabectedin. The SPD model was subsequently incorporated into our previously-established cell cycle model, forming a comprehensive, multi-scale quantification platform for evaluating drug effects across multiple scales, spanning the proteomic-, cellular-, and subcellular levels. This approach provides a quantitative mechanistic framework for evaluating drug-drug interactions in combination chemotherapy, and could potentially serve as a tool to predict combinatorial efficacy and assist in target selection.