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Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

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Item Type:Article
Title:Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC
Creators Name:Lankes, K. and Hassan, Z.Z. and Doffo, M.J. and Schneeweis, C. and Lier, S. and Öllinger, R. and Rad, R. and Krämer, O.H. and Keller, U. and Saur, D. and Reichert, M. and Schneider, G. and Wirth, M.
Abstract:The myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target, therefore identifying druggable synthetic lethal interactions in MYC-active PDAC may lead to novel precise therapies. First, to identify networks with hyperactive MYC, we profiled transcriptomes of established human cell lines, murine primary PDAC cell lines and accessed publicly available repositories to analyze transcriptomes of primary human PDAC. Networks active in MYC hyperactive subtypes were analyzed by gene set enrichment analysis. Next, we performed an unbiased pharmacological screen to define MYC-associated vulnerabilities. Hits were validated by analysis of drug-response repositories and genetic gain- and loss-of-function experiments. In these experiments, we discovered that the proteasome inhibitor Bortezomib triggers a MYC-associated vulnerability. In addition, by integrating publicly available data, we found the unfolded protein response as a signature connected to MYC. Furthermore, increased sensitivity of MYC-hyperactive PDACs to Bortezomib was validated in genetically modified PDAC cells. In sum, we provide evidence that perturbing the ubiquitin proteasome system might be an option to target MYC hyperactive PDAC cells. Our data provide the rationale to further develop precise targeting of the ubiquitin-proteasome system as a subtype-specific therapeutic approach.
Keywords:MYC, Pancreatic Cancer, UPR, UPS, Proteasome Inhibitor, Apoptosis
Source:Molecular Oncology
Page Range:3048-3064
Date:December 2020
Official Publication:https://doi.org/10.1002/1878-0261.12835
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/19140/Preprint version

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