Abstract
Small molecule screens are widely used to prioritize pharmaceutical development. However, determining the pathways targeted by these molecules is challenging, since the compounds are often promiscuous. We present a network strategy that takes into account the polypharmacology of small molecules in order to generate hypotheses for their broader mode of action. We report a screen for kinase inhibitors that increase the efficacy of gemcitabine, the first-line chemotherapy for pancreatic cancer. Eight kinase inhibitors emerge that are known to affect 201 kinases, of which only three kinases have been previously identified as modifiers of gemcitabine toxicity. In this work, we use the SAMNet algorithm to identify pathways linking these kinases and genetic modifiers of gemcitabine toxicity with transcriptional and epigenetic changes induced by gemcitabine that we measure using DNaseI-seq and RNA-seq. SAMNet uses a constrained optimization algorithm to connect genes from these complementary datasets through a small set of protein-protein and protein-DNA interactions. The resulting network recapitulates known pathways including DNA repair, cell proliferation and the epithelial-to-mesenchymal transition. We use the network to predict genes with important roles in the gemcitabine response, including six that have already been shown to modify gemcitabine efficacy in pancreatic cancer and ten novel candidates. Our work reveals the important role of polypharmacology in the activity of these chemosensitizing agents.
Highlights
Small molecule screens are a powerful tool to identify compounds that modify disease progression either directly or by synergistic action with existing drugs [1], [2]
We defined our hits as those kinase inhibitors that produced a reduction in survival by more than 30% when combined with gemcitabine versus when combined with a vehicle control
We will refer to these affected kinases as kinase hits, as they are directly targeted by the kinase inhibitor hits from our small molecule screen
Summary
Small molecule screens are a powerful tool to identify compounds that modify disease progression either directly or by synergistic action with existing drugs [1], [2]. We report a screen identifying kinase inhibitors that improve the efficacy of gemcitabine in pancreatic cancer. As is typically the case in such screens, the compounds are often reported as each having one or at most a few target kinases, their actual effects are much broader. The most commonly used chemotherapeutic agent in pancreatic cancer treatment is gemcitabine, a nucleoside analogue, which infiltrates the cell’s nucleotide metabolism, causing DNA damage and apoptosis [5]. Despite its wide use, gemcitabine shows limited efficacy: only 20%-30% of cases show a response, and this response consists of only a minor increase in survival time and symptom alleviation after exposure to gemcitabine [4]. Given the urgent need for improved therapies, there has been considerable interest in identifying drugs that could function to improve the efficacy of gemcitabine
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