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

• Published in: Gut Vol. 73; no. 9; pp. 1509 - 1528
• Main Authors: Vogt, Markus, Dudvarski Stankovic, Nevenka, Cruz Garcia, Yiliam, Hofstetter, Julia, Schneider, Katharina, Kuybu, Filiz, Hauck, Theresa, Adhikari, Bikash, Hamann, Anton, Rocca, Yamila, Grysczyk, Lara, Martin, Benedikt, Gebhardt-Wolf, Anneli, Wiegering, Armin, Diefenbacher, Markus, Gasteiger, Georg, Knapp, Stefan, Saur, Dieter, Eilers, Martin, Rosenfeldt, Mathias, Erhard, Florian, Vos, Seychelle M, Wolf, Elmar
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.09.2024; BMJ Publishing Group LTD
• Subjects: Adenocarcinoma; Animals; ATPases Associated with Diverse Cellular Activities - genetics; ATPases Associated with Diverse Cellular Activities - metabolism; Auxins; Cancer therapies; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; DNA Helicases - genetics; DNA Helicases - metabolism; Gene expression; GENE REGULATION; GENE TARGETING; Genetic screening; Humans; IMMUNOTHERAPY; Metastases; Mice; Mutation; Myc protein; ONCOGENES; Pancreas; PANCREATIC CANCER; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Targeted cancer therapy; Transcription factors; Tumors; ONCOGENES; GENE REGULATION; IMMUNOTHERAPY; PANCREATIC CANCER; GENE TARGETING
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2023-331519

ObjectiveThe 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).DesignTo 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.ResultsUnexpectedly, 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.ConclusionOne 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.