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

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

doi:10.1016/j.xgen.2025.100876

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

Chelsea E. Cunningham
, Frederick S. Vizeacoumar
, Yue Zhang
, Liliia Kyrylenko
, Simon Both
, Vincent Maranda
, He Dong
, Jared D.W. Price
, Peng Gao
, Konrad Wagner
, Yingwen Wu
, Mary Lazell-Wright
, Ashtalakshmi Ganapathysamy
, Rithik Hari
, Kalpana K. Bhanumathy
, Connor Denomy
, Anjali Saxena
, Jeff P. Vizeacoumar
, Alain Morejon Morales
, Faizaan Khan

Shayla Mosley, Angie Chen, Tetiana Katrii, Ben G.E. Zoller, Karthic Rajamanickam, Prachi Walke, Lihui Gong, Hardikkumar Patel, Hussain Elhasasna, Renuka Dahiya, Omar Abuhussein, Anton Dmitriev, Tanya Freywald, Erika Prando Munhoz, Eytan Ruppin, Joo Sang Lee, Katharina Rox, Martin Koebel, Laura Hopkins, Cheng Han Lee, Sunil Yadav, Gilles Gasparoni, Jörn Walter, Anand Krishnan, Raju Datla, Behzad Toosi, Kristi Baker, Jalna Meens, David W. Cescon, Laurie Ailles, Scot C. Leary, Yuliang Wu, Martin Empting, Alexandra K. Kiemer, Andrew Freywald, Franco J. Vizeacoumar

University of Saskatchewan
Saarland University
Agriculture and Agri-Food Canada
Saarland University
University of Alberta
National Institutes of Health
University of Maryland, College Park
Sungkyunkwan University
Helmholtz Centre for Infection Research
University of Calgary
Princess Margaret Cancer Centre
Center for Gender-Specific Biology and Medicine (CGBM)
Saskatchewan Cancer Agency

Research output: Contribution to journal › Article › peer-review

3 Scopus 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.

Original language	English
Article number	100876
Journal	Cell Genomics
Volume	5
Issue number	6
DOIs	https://doi.org/10.1016/j.xgen.2025.100876
State	Published - 11 Jun 2025
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

IGF2BP2
IMP2
PLK1
chromosomal instability
in vivo CRISPR screen
perturb-seq
single-cell CRISPR screening
synthetic dosage lethality
tumor heterogeneity

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10.1016/j.xgen.2025.100876

Cite this

Cunningham, C. E., Vizeacoumar, F. S., Zhang, Y., Kyrylenko, L., Both, S., Maranda, V., Dong, H., Price, J. D. W., Gao, P., Wagner, K., Wu, Y., Lazell-Wright, M., Ganapathysamy, A., Hari, R., Bhanumathy, K. K., Denomy, C., Saxena, A., Vizeacoumar, J. P., Morales, A. M., ... Vizeacoumar, F. J. (2025). Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality. Cell Genomics, 5(6), Article 100876. https://doi.org/10.1016/j.xgen.2025.100876

@article{e2b1c3dadff84085bfa24bf405142ce3,

title = "Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality",

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.",

keywords = "IGF2BP2, IMP2, PLK1, chromosomal instability, in vivo CRISPR screen, perturb-seq, single-cell CRISPR screening, synthetic dosage lethality, tumor heterogeneity",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = jun,

day = "11",

doi = "10.1016/j.xgen.2025.100876",

language = "English",

volume = "5",

journal = "Cell Genomics",

issn = "2666-979X",

publisher = "Cell Press",

number = "6",

}

Cunningham, CE, Vizeacoumar, FS, Zhang, Y, Kyrylenko, L, Both, S, Maranda, V, Dong, H, Price, JDW, Gao, P, Wagner, K, Wu, Y, Lazell-Wright, M, Ganapathysamy, A, Hari, R, Bhanumathy, KK, Denomy, C, Saxena, A, Vizeacoumar, JP, Morales, AM, Khan, F, Mosley, S, Chen, A, Katrii, T, Zoller, BGE, Rajamanickam, K, Walke, P, Gong, L, Patel, H, Elhasasna, H, Dahiya, R, Abuhussein, O, Dmitriev, A, Freywald, T, Munhoz, EP, Ruppin, E, Lee, JS, Rox, K, Koebel, M, Hopkins, L, Lee, CH, Yadav, S, Gasparoni, G, Walter, J, Krishnan, A, Datla, R, Toosi, B, Baker, K, Meens, J, Cescon, DW, Ailles, L, Leary, SC, Wu, Y, Empting, M, Kiemer, AK, Freywald, A & Vizeacoumar, FJ 2025, 'Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality', Cell Genomics, vol. 5, no. 6, 100876. https://doi.org/10.1016/j.xgen.2025.100876

TY - JOUR

T1 - Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

AU - Cunningham, Chelsea E.

AU - Vizeacoumar, Frederick S.

AU - Zhang, Yue

AU - Kyrylenko, Liliia

AU - Both, Simon

AU - Maranda, Vincent

AU - Dong, He

AU - Price, Jared D.W.

AU - Gao, Peng

AU - Wagner, Konrad

AU - Wu, Yingwen

AU - Lazell-Wright, Mary

AU - Ganapathysamy, Ashtalakshmi

AU - Hari, Rithik

AU - Bhanumathy, Kalpana K.

AU - Denomy, Connor

AU - Saxena, Anjali

AU - Vizeacoumar, Jeff P.

AU - Morales, Alain Morejon

AU - Khan, Faizaan

AU - Mosley, Shayla

AU - Chen, Angie

AU - Katrii, Tetiana

AU - Zoller, Ben G.E.

AU - Rajamanickam, Karthic

AU - Walke, Prachi

AU - Gong, Lihui

AU - Patel, Hardikkumar

AU - Elhasasna, Hussain

AU - Dahiya, Renuka

AU - Abuhussein, Omar

AU - Dmitriev, Anton

AU - Freywald, Tanya

AU - Munhoz, Erika Prando

AU - Ruppin, Eytan

AU - Lee, Joo Sang

AU - Rox, Katharina

AU - Koebel, Martin

AU - Hopkins, Laura

AU - Lee, Cheng Han

AU - Yadav, Sunil

AU - Gasparoni, Gilles

AU - Walter, Jörn

AU - Krishnan, Anand

AU - Datla, Raju

AU - Toosi, Behzad

AU - Baker, Kristi

AU - Meens, Jalna

AU - Cescon, David W.

AU - Ailles, Laurie

AU - Leary, Scot C.

AU - Wu, Yuliang

AU - Empting, Martin

AU - Kiemer, Alexandra K.

AU - Freywald, Andrew

AU - Vizeacoumar, Franco J.

PY - 2025/6/11

Y1 - 2025/6/11

N2 - 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.

AB - 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.

KW - IGF2BP2

KW - IMP2

KW - PLK1

KW - chromosomal instability

KW - in vivo CRISPR screen

KW - perturb-seq

KW - single-cell CRISPR screening

KW - synthetic dosage lethality

KW - tumor heterogeneity

UR - https://www.scopus.com/pages/publications/105004707708

U2 - 10.1016/j.xgen.2025.100876

DO - 10.1016/j.xgen.2025.100876

M3 - Article

AN - SCOPUS:105004707708

SN - 2666-979X

VL - 5

JO - Cell Genomics

JF - Cell Genomics

IS - 6

M1 - 100876

ER -

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

Abstract

UN SDGs

Keywords

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