Abstract
Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic cancer cells, which was shown previously to be synergistic. A total of 4069 drug-responsive proteins were identified and quantified in a time-series proteome analysis. This rich dataset provides broad views and accurate quantification of signaling pathways. Pathways relating to DNA damage response regulations, DNA repair, anti-apoptosis, pro-migration/invasion were implicated as underlying mechanisms for gemcitabine resistance and for the beneficial effects of the drug combination. Promising drug targets were identified for future investigation. This study also provides a database for systems mathematical modeling to relate drug effects and interactions in various signaling pathways in pancreatic cancer cells.
Highlights
Pancreatic cancer is one of the most lethal malignancies, with 5-year survival of only 8% (Siegel et al, 2016)
Despite various upstream stimuli activated by the two drugs in the MAPK pathway, western blot analysis revealed that gemcitabine induced only a slight increase in the downstream p38 phosphorylation, and the effect of birinapant alone on p38 was slight and limited to early time points (Figure 4A)
This study extends our previous investigation of the mechanisms of gemcitabine and birinapant actions and interactions
Summary
Pancreatic cancer is one of the most lethal malignancies, with 5-year survival of only 8% (Siegel et al, 2016). Comprehensive evaluation of the pancreatic cancer genome detected >1000 mutations categorized into 14 core signaling pathways, including DNA damage control and apoptosis (Jones et al, 2008; Yachida and Iacobuzio-Donahue, 2013). These pathways usually are functionally redundant, and pharmacological inhibition of individual nodes in one pathway can lead to activation of alternative pathways and induce drug resistance. Birinapant (TL32711; Tetralogic, Malvern, PA, United States) is a bivalent investigational antagonist of inhibitor of apoptosis proteins (IAP) It mimics the action of the second mitochondria-derived activator of caspase, and has showed clinical activity in hematological malignancies and solid tumors as a single agent and in combination with other chemotherapeutics. Mechanisms related to gemcitabine resistance are explored and promising signaling pathways are proposed as drug targets
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