Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

Chromosomal instability (CIN) drives tumor heterogeneity, complicating cancer therapy. Although Polo-like kinase 1 (PLK1) overexpression induces CIN, direct inhibition of PLK1 has shown limited clinical benefits. We therefore performed a genome-wide synthetic dosage lethality (SDL) screen to identify effective alternative targets and validated over 100 candidates using in vivo and in vitro secondary CRISPR screens. We employed direct-capture Perturb-seq to assess the transcriptional consequences and viability of each SDL perturbation at a single-cell resolution. This revealed IGF2BP2 as a critical genetic dependency that, when targeted, downregulated PLK1 and significantly restricted tumor growth. Mechanistic analyses showed that IGF2BP2 loss disrupted cellular energy metabolism and mitochondrial ATP production by downregulating PLK1 levels as well as genes associated with oxidative phosphorylation. Consistent with this, pharmacological inhibition of IGF2BP2 severely impacts the viability of PLK1-overexpressing cancer cells addicted to higher metabolic rates. Our work offers a novel therapeutic strategy against PLK1-driven heterogeneous malignancies.

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Publication Details

Journal
Cell Genomics
Published
2025-05-09
DOI
https://doi.org/10.1016/j.xgen.2025.100876
Citations
3
Primary Topic
Microtubule and mitosis dynamics
Type
article
Field-Weighted Citation Impact
3.45
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article

Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

Andrew Freywald, Tanya Freywald, Anand Krishnan, Connor Denomy et al.
3 citations
Cell Genomics
Microtubule and mitosis dynamics
3.45
article

Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

Andrew Freywald, Tanya Freywald, Anand Krishnan, Connor Denomy, Gilles Gasparoni, Hussain Elhasasna, Simon Both, A. Chen, Prachi Walke, Vincent Maranda, Konrad Wagner, Frederick S. Vizeacoumar, Katharina Rox, Jalna Meens, Joo Sang Lee, Raju Datla, Scot C. Leary, Faizaan Khan, Alain Morejon Morales, Kalpana K. Bhanumathy, Behzad M. Toosi, Martin Empting, Alexandra K. Kiemer, Yingwen Wu, Omar Abuhussein, David W. Cescon, Anjali Saxena, Karthic Rajamanickam, Yuliang Wu, Ben G. E. Zoller, Anton E. Dmitriev, Renuka Dahiya, Kristi Baker, Shayla R. Mosley, Chelsea E. Cunningham, Érika Prando Munhoz, Laurie Ailles, Franco J. Vizeacoumar, Sunil Yadav, He Dong, Yue Zhang, Peng Gao, Cheng‐Han Lee, Laura Hopkins, Mary Lazell-Wright, Liliia Kyrylenko, Ashtalakshmi Ganapathysamy, Hardikkumar Patel, Eytan Ruppin, Jörn Walter, Tetiana Katrii, Rithik Hari, Jared D.W. Price, Lihui Gong, Martin Köebel, Jeff Patrick Vizeacoumar
article en
3 citations

Abstract

Chromosomal instability (CIN) drives tumor heterogeneity, complicating cancer therapy. Although Polo-like kinase 1 (PLK1) overexpression induces CIN, direct inhibition of PLK1 has shown limited clinical benefits. We therefore performed a genome-wide synthetic dosage lethality (SDL) screen to identify effective alternative targets and validated over 100 candidates using in vivo and in vitro secondary CRISPR screens. We employed direct-capture Perturb-seq to assess the transcriptional consequences and viability of each SDL perturbation at a single-cell resolution. This revealed IGF2BP2 as a critical genetic dependency that, when targeted, downregulated PLK1 and significantly restricted tumor growth. Mechanistic analyses showed that IGF2BP2 loss disrupted cellular energy metabolism and mitochondrial ATP production by downregulating PLK1 levels as well as genes associated with oxidative phosphorylation. Consistent with this, pharmacological inhibition of IGF2BP2 severely impacts the viability of PLK1-overexpressing cancer cells addicted to higher metabolic rates. Our work offers a novel therapeutic strategy against PLK1-driven heterogeneous malignancies.

Cell GenomicsVol. 5(6)
University of Maryland, Baltimore (US), University Health Network (CA), Agriculture and Agri-Food Canada (CA), Cameco (Canada) (CA), University of Alberta (CA), University of Calgary (CA), Princess Margaret Cancer Centre (CA), University of Saskatchewan (CA), Saskatchewan Cancer Agency (CA), Helmholtz Centre for Infection Research (DE), National Cancer Institute (US), Helmholtz Institute for Pharmaceutical Research Saarland (DE), Global Institute for Water Security (CA), University of Maryland, College Park (US), Saarland University (DE)
Openalex Percentile: Top 9%
Microtubule and mitosis dynamics
3.45
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