️ 69: Synthetic Dosage Lethality of PLK1 — Targetable Vulnerabilities in PLK1-Overexpressing Cancers

️ Episode 69: Synthetic Dosage Lethality of PLK1 — Targetable Vulnerabilities in PLK1-Overexpressing Cancers In this episode of Base por Base, we delve into a comprehensive study by Cunningham et al. (2025) in Cell Genomics that harnesses genome-wide synthetic dosage lethality (SDL) screening to uncover novel therapeutic targets in cancers driven by Polo-like kinase 1 (PLK1). By integrating pooled shRNA and CRISPR-Cas9 screens in both in vitro and in vivo patient-derived xenograft models, followed by single-cell Perturb-seq analysis, the authors identify IGF2BP2 as a critical dependency in PLK1-overexpressing tumor cells. Mechanistic investigations reveal that loss of IGF2BP2 not only destabilizes PLK1 mRNA via disrupted m6A-mediated binding but also impairs mitochondrial oxidative phosphorylation, collectively crippling the energy metabolism of malignant cells. Finally, the first small-molecule inhibitors of IGF2BP2 recapitulate these effects, suppressing tumor growth in xenograft and PDX models and offering a dual-mechanism strategy to overcome tumor heterogeneity . Highlights of the study:Synthetic dosage lethality screening pinpoints IGF2BP2 loss as selectively lethal to PLK1-overexpressing cells.Disruption of IGF2BP2 reduces PLK1 transcript and protein abundance by impairing m6A-dependent mRNA stabilization.IGF2BP2 deficiency downregulates key oxidative phosphorylation genes, diminishing mitochondrial ATP production.Pharmacological inhibition of IGF2BP2 mimics genetic knockout, decreasing cellular respiration and inducing apoptosis in PLK1-high models.Combined genetic and chemical targeting of IGF2BP2 effectively suppresses tumor growth in multiple breast cancer xenograft and PDX systems. Conclusion:This work establishes IGF2BP2 as a synthetic lethal partner of PLK1, offering a two-pronged attack—downregulation of PLK1 and collapse of mitochondrial bioenergetics—to selectively target PLK1-overexpressing cancers. The identification of IGF2BP2 inhibitors lays the groundwork for precision therapies aimed at overcoming intratumoral heterogeneity in PLK1-driven malignancies. Reference:Cunningham, C. E., Vizeacoumar, F. S., Zhang, Y., et al. (2025). Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality. Cell Genomics, 5, 100876. 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 (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

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