dc.contributor.author
Lankes, Katharina
dc.contributor.author
Hassan, Zonera
dc.contributor.author
Doffo, María Josefina
dc.contributor.author
Schneeweis, Christian
dc.contributor.author
Lier, Svenja
dc.contributor.author
Öllinger, Rupert
dc.contributor.author
Rad, Roland
dc.contributor.author
Krämer, Oliver H.
dc.contributor.author
Keller, Ulrich
dc.contributor.author
Saur, Dieter
dc.contributor.author
Reichert, Maximilian
dc.contributor.author
Schneider, Günter
dc.contributor.author
Wirth, Matthias
dc.date.accessioned
2021-11-16T10:36:35Z
dc.date.available
2021-11-16T10:36:35Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/32726
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-32452
dc.description.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 (UPS) might be an option to target MYC-hyperactive PDAC cells. Our data provide the rationale to further develop precise targeting of the UPS as a subtype-specific therapeutic approach.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
pancreatic cancer
en
dc.subject
proteasome inhibitor
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Targeting the ubiquitin‐proteasome system in a pancreatic cancer subtype with hyperactive MYC
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1002/1878-0261.12835
dcterms.bibliographicCitation.journaltitle
Molecular Oncology
dcterms.bibliographicCitation.number
12
dcterms.bibliographicCitation.originalpublishername
Wiley
dcterms.bibliographicCitation.pagestart
3048
dcterms.bibliographicCitation.pageend
3064
dcterms.bibliographicCitation.volume
14
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
DEAL Wiley
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
33099868
dcterms.isPartOf.eissn
1878-0261