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

Author

Listed:
  • Jana Koch

    (Technical University of Munich
    University of Tübingen)

  • Sebastian J. Schober

    (Technical University of Munich)

  • Sruthi V. Hindupur

    (Technical University of Munich)

  • Caroline Schöning

    (Technical University of Munich)

  • Florian G. Klein

    (Technical University of Munich)

  • Klaus Mantwill

    (Technical University of Munich)

  • Maximilian Ehrenfeld

    (Technical University of Munich)

  • Ulrike Schillinger

    (Technical University of Munich)

  • Timmy Hohnecker

    (Technical University of Munich)

  • Pan Qi

    (Technical University of Munich
    Shanghai Jiao Tong University)

  • Katja Steiger

    (Technical University of Munich)

  • Michaela Aichler

    (Research Unit Analytical Pathology)

  • Jürgen E. Gschwend

    (Technical University of Munich)

  • Roman Nawroth

    (Technical University of Munich)

  • Per Sonne Holm

    (Technical University of Munich
    Medical University Innsbruck)

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.

Suggested Citation

  • Jana Koch & Sebastian J. Schober & Sruthi V. Hindupur & Caroline Schöning & Florian G. Klein & Klaus Mantwill & Maximilian Ehrenfeld & Ulrike Schillinger & Timmy Hohnecker & Pan Qi & Katja Steiger & M, 2022. "Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32087-5
    DOI: 10.1038/s41467-022-32087-5
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    References listed on IDEAS

    as
    1. Shom Goel & Molly J. DeCristo & April C. Watt & Haley BrinJones & Jaclyn Sceneay & Ben B. Li & Naveed Khan & Jessalyn M. Ubellacker & Shaozhen Xie & Otto Metzger-Filho & Jeremy Hoog & Matthew J. Ellis, 2017. "CDK4/6 inhibition triggers anti-tumour immunity," Nature, Nature, vol. 548(7668), pages 471-475, August.
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