2. Academic Validation
  3. Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus

Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus

  • Nat Commun. 2022 Aug 10;13(1):4689. doi: 10.1038/s41467-022-32087-5.
Jana Koch  # 1 2,  Sebastian J Schober  # 3,  Sruthi V Hindupur  # 1,  Caroline Schöning 3,  Florian G Klein 1,  Klaus Mantwill 1,  Maximilian Ehrenfeld 1,  Ulrike Schillinger 1,  Timmy Hohnecker 1,  Pan Qi 1 4,  Katja Steiger 5,  Michaela Aichler 6,  Jürgen E Gschwend 1,  Roman Nawroth 7,  Per Sonne Holm 8 9
Affiliations

Affiliations

  • 1 Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 2 Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, University of Tübingen, Tübingen, Germany.
  • 3 Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804, Munich, Germany.
  • 4 Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 5 Department of Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 6 Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit Analytical Pathology, Munich, Germany.
  • 7 Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. roman.nawroth@tum.de.
  • 8 Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. per-sonne.holm@i-med.ac.at.
  • 9 Department of Oral and Maxillofacial Surgery, Medical University Innsbruck, A-6020, Innsbruck, Austria. per-sonne.holm@i-med.ac.at.
  • # Contributed equally.
PMID: 35948546 DOI: 10.1038/s41467-022-32087-5
Abstract

CDK4/6 inhibitors (CDK4/6i) and oncolytic viruses are promising therapeutic agents for the treatment of various cancers. As single agents, CDK4/6 inhibitors that are approved for the treatment of breast Cancer in combination with endocrine therapy cause G1 cell cycle arrest, whereas adenoviruses induce progression into S-phase in infected cells as an integral part of the their life cycle. Both CDK4/6 inhibitors and adenovirus replication target the Retinoblastoma protein albeit for different purposes. Here we show that in combination CDK4/6 inhibitors potentiate the anti-tumor effect of the oncolytic adenovirus XVir-N-31 in bladder Cancer and murine Ewing sarcoma xenograft models. This increase in oncolytic potency correlates with an increase in virus-producing Cancer cells, enhanced viral genome replication, particle formation and consequently Cancer cell killing. The molecular mechanism that regulates this response is fundamentally based on the reduction of Retinoblastoma protein expression levels by CDK4/6 inhibitors.

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