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

Markus Vogt, Nevenka Dudvarski Stankovic, Yiliam Cruz Garcia, Julia Hofstetter, Katharina Schneider, Filiz Kuybu, Theresa Hauck, Bikash Adhikari, Anton Hamann, Yamila Rocca, Lara Grysczyk, Benedikt Martin, Anneli Gebhardt-Wolf, Armin Wiegering, Markus Diefenbacher, Georg Gasteiger, Stefan Knapp, Dieter Saur, Martin Eilers, Mathias RosenfeldtFlorian Erhard, Seychelle M. Vos, Elmar Wolf

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbergutjnl-2023-331519
JournalGut
DOIs
StateAccepted/In press - 2024
Externally publishedYes

Keywords

  • GENE REGULATION
  • GENE TARGETING
  • IMMUNOTHERAPY
  • ONCOGENES
  • PANCREATIC CANCER

Fingerprint

Dive into the research topics of 'Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2'. Together they form a unique fingerprint.

Cite this