Journal
ACS CHEMICAL BIOLOGY
Volume 17, Issue 12, Pages 3290-3297Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.2c00710
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Funding
- Mallinckrodt Foundation
- N.I.H [K22CA201103, R35GM124838]
- [R01DK118946]
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This study uncovers a link between autophagy and cell cycle progression and explores the inhibition of autophagy in pancreatic cancer cells using selective small molecule inhibitors. Additionally, new combination treatments were discovered through an unbiased screen.
Autophagy is a conserved metabolic pathway that is central to many diseases. Recently, there has been a lot of interest in targeting autophagy with small molecule inhibitors as a possible therapeutic strategy. However, many of the compounds used for autophagy are nonselective. Here, we explored the inhibition of autophagy in pancreatic cancer cells using established selective small molecule inhibitors and discovered an unexpected link between the autophagy pathway and progression through the cell cycle. Our findings revealed that treatments with inhibitors that have different autophagy pathway targets block cell replication and activate other metabolic pathways to compensate for the blockade in autophagy. An unbiased screen looking for known drugs that might synergize with autophagy inhibition revealed new combination treatments that might provide a blueprint for therapeutic approaches to pancreatic cancer. The drugs quizartinib and THZ1 showed a strong synergistic effect in pancreatic cells with autophagy inhibition.
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