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Impact of sequencing of androgen receptor-signaling inhibition and radiotherapy in prostate cancer: importance of homologous recombination disruption

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Abstract

Purpose

The synergy of combining androgen receptor-signaling inhibition (ARSI) to radiotherapy (RT) in prostate cancer has been largely attributed to non-homologous end joining (NHEJ) inhibition. However, this mechanism is unlikely to explain recently observed trial results that demonstrated the sequencing of ARSI and RT significantly impacts clinical outcomes, with adjuvant ARSI following RT yielding superior outcomes to neoadjuvant/concurrent therapy. We hypothesized this is driven by differential effects on AR-signaling and alternative DNA repair pathway engagement based on ARSI/RT sequencing.

Methods

We explored the effects of ARSI sequencing with RT (neoadjuvant vs concurrent vs adjuvant) in multiple prostate cancer cell lines using androgen-deprived media and validation with the anti-androgen enzalutamide. The effects of ARSI sequencing were measured with clonogenic assays, AR-target gene transcription and translation quantification, cell cycle analysis, DNA damage and repair assays, and xenograft animal validation studies.

Results

Adjuvant ARSI after RT was significantly more effective at killing colony forming cells and decreasing the transcription and translation of downstream AR-target genes across all prostate cancer models evaluated. These results were reproduced in xenograft studies. The differential effects of ARSI sequencing were not fully explained by NHEJ inhibition alone, but by the additional disruption of homologous recombination specifically with adjuvant sequencing of ARSI.

Conclusion

We demonstrate that altered sequencing of ARSI and RT mediates differential anti-AR-signaling and anti-cancer effects, with the greatest benefit from adjuvant ARSI following RT. These results, combined with our prior clinical findings, support the superiority of an adjuvant-based sequencing approach when using ARSI with RT.

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Data availability

All relevant data and protocols are included in the Supplementary Information.

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Acknowledgements

This work was funded by Genotoxic Stress and Androgen Receptor Signaling: Integration of Dynamic Non-invasive Biomarkers Post-Radiotherapy in Prostate Cancer Army-DoD-US (PC151068).

Funding

This study was funded by Genotoxic Stress and Androgen Receptor Signaling: Integration of Dynamic Non-invasive Biomarkers Post-Radiotherapy in Prostate Cancer Army-DoD-US (Grant number PC151068, DE Spratt).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Steven G. Allen, Chao Zhang, Robert T. Dess & William C. Jackson

  2. Department of Radiation Oncology, The Ottawa Hospital Cancer Center, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Shawn Malone & Soumyajit Roy

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Rohit Mehra

  4. Department of Radiation Oncology, UH Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Corey Speers & Daniel E. Spratt

  5. Rogel Cancer Center and Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA

    Arul M. Chinnaiyan

  6. Department of Population Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Yilun Sun

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  1. Steven G. Allen
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Contributions

SGA: Project Development, Data Collection, Data Analysis, Manuscript Writing/Editing. CZ: Project Development, Data Collection, Data Analysis, Manuscript Writing/Editing. SM: Project Development, Data Analysis, Manuscript Writing/Editing. SR: Data Analysis, Manuscript Editing. RTD: Manuscript Editing. WCJ: Data Analysis, Manuscript Editing. RM: Manuscript Editing. CS: Project Development, Data Analysis, Manuscript Editing. AMC: Project Development, Data Analysis, Manuscript Editing. YS: Manuscript Editing. DES: Project Development, Data Analysis, Manuscript Writing/Editing.

Corresponding author

Correspondence to Daniel E. Spratt.

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Conflict of interest

SM has received honoraria from Janssen, Astellas, AstraZeneca, AMGEN, Abbvie, Knight Therapeutics, and Bayer and travel support from TerSera and Sanofi. CS has a grant from the NCI to study AR-mediated radiosensitization in breast cancer. AMC has grant funding from the Howard Hughes Medical Institute and Prostate Cancer Foundation; receives royalties from Genome Dx and Hologic; receives consulting fees from Ascentage Pharma, Lynx Dx, RAAPTA, Esanik Therapeutics, Inc, Proteovant, and Flamingo Therapeutics; and holds stock options in Tempus, Inc, Lynx Dx, RAAPTA, Esanik Therapeutics, Inc, EdenRoc, Flamingo Therapeutics, and GenePath Dx. DES received honoraria from Bayer, Blue Earth, Boston Scientific, Myovant, Novartis, and Pfizer. SGA, CZ, SR, RTD, WCJ, RM, and YS have no interests to declare.

Compliance with ethical standards

All animal experiments were performed with the approval of the University of Michigan Institutional Animal Care and Use Committee in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. The ARRIVE guidelines 2.0 were used in reporting the results.

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Allen, S.G., Zhang, C., Malone, S. et al. Impact of sequencing of androgen receptor-signaling inhibition and radiotherapy in prostate cancer: importance of homologous recombination disruption. World J Urol 41, 3877–3887 (2023). https://doi.org/10.1007/s00345-023-04649-9

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