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

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, Michaela Aichler, Jürgen E. Gschwend, Roman Nawroth () and Per Sonne Holm ()
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Jana Koch: Technical University of Munich
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32087-5

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