LC-MS/MS analyses of human PDAC cell lines after treatment with a new SUMO inhibitor
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Elite
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Pancreatic Ductal Adenocarcinoma Cell, Permanent Cell Line Cell, Cell Culture
DISEASE(S): Pancreatic Ductal Adenocarcinoma
SUBMITTER: 
Kathrin Schunck
LAB HEAD: Prof. Dr. Ulrich Keller
PROVIDER: PXD011347 | Pride | 2020-01-06
REPOSITORIES: Pride
Dataset's files
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| 20180316_GT_KK_Ex238_1.raw | Raw | |||
| 20180316_GT_KK_Ex238_10.raw | Raw | |||
| 20180316_GT_KK_Ex238_11.raw | Raw | |||
| 20180316_GT_KK_Ex238_12.raw | Raw | |||
| 20180316_GT_KK_Ex238_13.raw | Raw |
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Project description:Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with overall five-year survival of 8%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC, however subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumor biology. It is clear that hyperactivation of MYC generates dependencies, which can be exploited therapeutically. To find MYC-associated dependency we analyzed human PDAC expression dataset. We observed that MYC is connected to the sumoylation machinery in PDAC. Components of the SUMO pathway mark a PDAC subtype with worse prognosis and we provide evidence that PDACs with a MYChigh/SUMOhigh phenotype respond to a novel SUMO inhibitor, offering the opportunity to develop novel stratified PDAC therapies
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Project description:Objective: The hallmark oncogene MYC drives the progression of most tumorstumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). Design: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumorstumours in mice.Results:Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumorstumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumortumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immuno-evasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. Conclusion: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.
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