69: PLK1 overexpression exposes an IGF2BP2 vulnerability

Cunningham C et al., Cell Genomics - This study used orthotopic breast PDX models, pooled and arrayed CRISPR/Cas9 screens, and Direct‑Capture Perturb‑seq to search for synthetic‑dosage‑lethal (SDL) partners of PLK1 across heterogeneous tumors. IGF2BP2 emerged as a top SDL hit using independent functional genomics approaches. Pharmacologic and genetic inhibition of IGF2BP2 impaired expansion of PLK1‑overexpressing tumors and altered stability of target mRNAs, supporting a mechanistic link. The work highlights a potential therapeutic strategy that targets a common vulnerability in PLK1‑high cancer cells despite intratumor heterogeneity. Key terms: PLK1, IGF2BP2, synthetic dosage lethality, CRISPR screen, breast PDX.

Study Highlights:
The authors combined pooled genome‑wide and arrayed CRISPR/Cas9 screens in breast PDX models with single‑cell Direct‑Capture Perturb‑seq to identify SDL interactions with PLK1. IGF2BP2 was repeatedly prioritized as a top SDL hit across independent screens. Functional follow‑up showed that inhibition of IGF2BP2 decreased expansion of PLK1‑overexpressing tumors and destabilized mRNAs linked to the PLK1 state. The results point to IGF2BP2 as a mechanistic and potentially druggable dependency in PLK1‑high tumors.

Conclusion:
Across multiple orthogonal in vivo and single‑cell genomic screens, IGF2BP2 is identified as a reproducible synthetic‑dosage‑lethal partner of PLK1; targeting IGF2BP2 reduces growth of PLK1‑overexpressing breast PDX tumors by perturbing mRNA stability pathways and may offer a strategy to exploit a shared vulnerability in heterogeneous cancers.

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Article title:
Three independent approaches identify IGF2BP2 as a top SDL target of PLK1

First author:
Cunningham C

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100876

Reference:
Cunningham C.E., Vizeacoumar F.S., Zhang Y., Kyrylenko L., Both S., Maranda V., et al.. Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality. Cell Genomics, 5, 100876. (2025). https://doi.org/10.1016/j.xgen.2025.100876

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-08.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing SDL concept, IGF2BP2 mechanism (PLK1 mRNA stability and OxPhos transcripts), Direct-Capture Perturb-seq validation, pharmacological inhibition with C4, in vivo breast cancer PDX findings, safety window vs normal cells, and study limitations.
- transcript topics: SDL-based identification of IGF2BP2 as PLK1 dependency; IGF2BP2's role in PLK1 mRNA stability; IGF2BP2's stabilization of OxPhos transcripts; Direct-Capture Perturb-seq validation across heterogeneous tumors; Pharmacological IGF2BP2 inhibition with compound C4; Selective toxicity and therapeutic window in normal vs cancer cells

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_...