Abstract
BackgroundFor most patients, pancreatic adenocarcinoma responds poorly to treatment, and novel therapeutic approaches are needed. Standard-of-care paclitaxel (PTX), combined with birinapant (BRP), a bivalent mimetic of the apoptosis antagonist SMAC (second mitochondria-derived activator of caspases), exerts synergistic killing of PANC-1 human pancreatic adenocarcinoma cells.MethodsTo investigate potential mechanisms underlying this synergistic pharmacodynamic interaction, data capturing PANC-1 cell growth, apoptosis kinetics, and cell cycle distribution were integrated with high-quality IonStar-generated proteomic data capturing changes in the relative abundance of more than 3300 proteins as the cells responded to the two drugs, alone and combined.ResultsPTX alone (15 nM) elicited dose-dependent G2/M-phase arrest and cellular polyploidy. Combined BRP/PTX (150/15 nM) reduced G2/M by 35% and polyploid cells by 45%, and increased apoptosis by 20%. Whereas BRP or PTX alone produced no change in the pro-apoptotic protein pJNK, and a slight increase in the anti-apoptotic protein Bcl2, the drug combination increased pJNK and decreased Bcl2 significantly compared to the vehicle control. A multi-scale, mechanism-based mathematical model was developed to investigate integrated birinapant/paclitaxel effects on temporal profiles of key proteins involved in kinetics of cell growth, death, and cell cycle distribution.ConclusionsThe model, consistent with the observed reduction in the Bcl2/BAX ratio, suggests that BRP-induced apoptosis of mitotically-arrested cells is a major contributor to the synergy between BRP and PTX. Coupling proteomic and cellular response profiles with multi-scale pharmacodynamic modeling provides a quantitative mechanistic framework for evaluating pharmacodynamically-based drug-drug interactions in combination chemotherapy, and could potentially guide the development of promising drug regimens.
Highlights
For most patients, pancreatic adenocarcinoma responds poorly to treatment, and novel therapeutic approaches are needed
pancreatic adenocarcinoma (PDAC) is not represented in the NCI-60 panel [5], and there is a paucity of data for PDAC, which typically harbors large numbers of mutations in numerous core signaling pathways [6,7,8]
In order to identify key points of drug interaction that underlie the observed drug synergy on pancreatic cancer cells, we developed quantitative pharmacodynamic and network interaction models as an approach to extract a more mechanistic understanding of the synergy from temporal changes in large-scale proteomic data
Summary
Pancreatic adenocarcinoma responds poorly to treatment, and novel therapeutic approaches are needed. Standard-of-care paclitaxel (PTX), combined with birinapant (BRP), a bivalent mimetic of the apoptosis antagonist SMAC (second mitochondria-derived activator of caspases), exerts synergistic killing of PANC-1 human pancreatic adenocarcinoma cells. The NCI ALMA NAC (A Large Matrix of Anti-Neoplastic Agent Combinations) project screened over 5000 pairs of 104 FDAapproved oncology drugs against the NCI-60 panel of human tumor cell lines to identify new, synergistic combinations [4]. Transcriptomic signatures of patient-derived organoids suggest potential biomarkers to predict chemosensitivity to FOLFIRINOX or GEM/ABX combinations [10]. This approach has yet to identify novel, clinically deployed combinations
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