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Vogt, M.A.* ; Dudvarski Stankovic, N.* ; Cruz Garcia, Y.* ; Hofstetter, J.* ; Schneider, K.* ; Kuybu, F.* ; Hauck, T.E.* ; Adhikari, B.* ; Hamann, A.* ; Rocca, Y.* ; Grysczyk, L.* ; Martin, B.* ; Gebhardt-Wolf, A.* ; Wiegering, A.* ; Diefenbacher, M. ; Gasteiger, G.* ; Knapp, S.* ; Saur, D.* ; Eilers, M.* ; Rosenfeldt, M.* ; Erhard, F.* ; Vos, S.M.* ; Wolf, E.*

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.

Gut, DOI: 10.1136/gutjnl-2023-331519 (2024)
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OBJECTIVE: The hallmark oncogene MYC drives the progression of most tumours, 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 tumours 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 tumours 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 tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene Regulation ; Gene Targeting ; Immunotherapy ; Oncogenes ; Pancreatic Cancer; Rna-polymerase-ii; Essential Cofactor; C-myc; Complex; Max; Adenocarcinoma; Transformation; Oncogene; Proteins; Driven
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0017-5749
e-ISSN 1468-3288
Journal Gut (eGut)
Publisher BMJ Publishing Group
Publishing Place British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-501694-001
Grants European Research Council
German Cancer Aid
German Research Foundation (DFG)
DOI 10.1136/gutjnl-2023-331519
WOS ID 001238809700001
Scopus ID 85195020059
PubMed ID 38821858
Erfassungsdatum 2024-07-25
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