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

Authors :
Martin F. Orth
Tilman L B Hölting
Cornelius M. Funk
Marlene Dallmayer
Aruna Marchetto
Thomas Kirchner
Maximilian M. L. Knott
Florencia Cidre-Aranaz
Uta Dirksen
Andreas Ranft
Julian Musa
Laura Romero-Pérez
Felix Bestvater
Thomas G. P. Grunewald
Ana Banito
Merve Kasan
Wolfgang Hartmann
Jing Li
Stefanie Stein
Roland Imle
Javier Alonso
Shunya Ohmura
Ana Sastre
Deutsche Krebshilfe
German Cancer Aid
Source :
Nature Communications, Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021), Repisalud, Instituto de Salud Carlos III (ISCIII)
Publication Year :
2021
Publisher :
Nature Publishing Group UK, 2021.

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.<br />In this study, the authors show that that oncogenic hijacking of PRC1 sensitizes genomically stable Ewing sarcoma cells for PLK1 inhibition alone or in synergy with a microtubule-destabilizing drug via induction of cytokinesis defects, rendering PRC1 a promising, broadly applicable predictive biomarker

Details

Language :
English
ISSN :
20411723
Volume :
12
Database :
OpenAIRE
Journal :
Nature Communications
Accession number :
edsair.doi.dedup.....909cbd8d20fa8876533f68b48a3b2e14