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

IF 11.1 Q1 CELL BIOLOGY

Cell genomics Pub Date : 2025-06-11 Epub Date: 2025-05-09 DOI:10.1016/j.xgen.2025.100876

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

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引用次数: 0

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.

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通过合成剂量致死性鉴定plk1过表达癌症的靶向脆弱性。

染色体不稳定性（CIN）驱动肿瘤异质性，使癌症治疗复杂化。虽然polo样激酶1 （PLK1）过表达可诱导CIN，但直接抑制PLK1已显示出有限的临床益处。因此，我们进行了全基因组合成剂量致死（SDL）筛选，以确定有效的替代靶点，并使用体内和体外二次CRISPR筛选验证了100多个候选靶点。我们采用直接捕获摄动序列（direct-capture Perturb-seq）在单细胞分辨率下评估每个SDL扰动的转录后果和生存能力。这表明IGF2BP2是一个关键的遗传依赖性，当靶向时，它下调PLK1并显著限制肿瘤生长。机制分析表明，IGF2BP2缺失通过下调PLK1水平以及与氧化磷酸化相关的基因，破坏细胞能量代谢和线粒体ATP产生。与此一致的是，IGF2BP2的药理抑制严重影响了依赖于高代谢率的plk1过表达癌细胞的生存能力。我们的工作为plk1驱动的异质性恶性肿瘤提供了一种新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell genomics

CiteScore

7.10

自引率

0.00%

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