Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer

Jing Li, Shunya Ohmura, Aruna Marchetto, Martin F. Orth, Roland Imle, Marlene Dallmayer, Julian Musa, Maximilian M. L. Knott, Tilman L. B. Hölting, Stefanie Stein, Cornelius M. Funk, Ana Sastre, Javier Alonso, Felix Bestvater, Merve Kasan, Laura Romero-Pérez, Wolfgang Hartmann, Andreas Ranft, Ana Banito, Uta Dirksen, Thomas Kirchner, Florencia Cidre-Aranaz and Thomas G. P. Grünewald ()
Additional contact information
Jing Li: LMU Munich
Shunya Ohmura: LMU Munich
Aruna Marchetto: LMU Munich
Martin F. Orth: LMU Munich
Roland Imle: Hopp Children’s Cancer Center (KiTZ)
Marlene Dallmayer: LMU Munich
Julian Musa: LMU Munich
Maximilian M. L. Knott: LMU Munich
Tilman L. B. Hölting: LMU Munich
Stefanie Stein: LMU Munich
Cornelius M. Funk: LMU Munich
Ana Sastre: Unidad Hemato-oncología Pediátrica, Hospital Infantil Universitario La Paz
Javier Alonso: Instituto de Salud Carlos III
Felix Bestvater: German Cancer Research Center (DKFZ)
Merve Kasan: LMU Munich
Laura Romero-Pérez: LMU Munich
Wolfgang Hartmann: University Hospital Münster
Andreas Ranft: University Hospital Essen
Ana Banito: Hopp Children’s Cancer Center (KiTZ)
Uta Dirksen: University Hospital Essen
Thomas Kirchner: LMU Munich
Florencia Cidre-Aranaz: LMU Munich
Thomas G. P. Grünewald: LMU Munich

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Chromosomal instability (CIN) is a hallmark of cancer1. Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably ‘silent’ genomes with minimal CIN2. Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe. Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials.

Date: 2021
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DOI: 10.1038/s41467-021-25553-z

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