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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality
Chelsea E Cunningham1, Frederick S Vizeacoumar2, Yue Zhang1
1Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
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.
Insights
Targeting IGF2BP2 offers a new strategy against cancers with chromosomal instability (CIN). Inhibiting IGF2BP2 reduces Polo-like kinase 1 (PLK1) levels, restricting tumor growth in CIN-driven malignancies.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Chromosomal instability (CIN) drives tumor heterogeneity and complicates cancer therapy.
- Polo-like kinase 1 (PLK1) overexpression induces CIN, but direct PLK1 inhibition has limited clinical success.
Purpose of the Study:
- To identify novel therapeutic targets for CIN-driven cancers by performing a genome-wide synthetic dosage lethality (SDL) screen.
- To uncover alternative strategies to target PLK1-overexpressing cancers.
Main Methods:
- Conducted a genome-wide SDL screen to identify synthetic lethal partners.
- Validated candidates using in vivo and in vitro CRISPR screens.
- Utilized direct-capture Perturb-seq for single-cell transcriptional and viability analysis.
Main Results:
- Identified Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a critical genetic dependency.
- Targeting IGF2BP2 downregulated PLK1 and genes involved in oxidative phosphorylation, disrupting cellular metabolism and ATP production.
- IGF2BP2 inhibition significantly restricted tumor growth in PLK1-overexpressing cancer cells.
Conclusions:
- IGF2BP2 is a novel therapeutic target for cancers exhibiting chromosomal instability.
- Targeting IGF2BP2 presents a promising strategy against PLK1-driven heterogeneous malignancies by disrupting energy metabolism.
