Author:
Cunningham Chelsea E.,Vizeacoumar Frederick S.,Zhang Yue,Kyrylenko Liliia,Gao Peng,Maranda Vincent,Dong He,Price Jared DW,Ganapathysamy Ashtalakshmi,Hari Rithik,Denomy Connor,Both Simon,Wagner Konrad,Wu Yingwen,Khan Faizaan,Mosley Shayla,Chen Angie,Katrii Tetiana,Zoller Ben G. E.,Rajamanickam Karthic,Walke Prachi,Gong Lihui,Patel Hardikkumar,Lazell-Wright Mary,Morales Alain Morejon,Bhanumathy Kalpana K.,Elhasasna Hussain,Dahiya Renuka,Abuhussein Omar,Dmitriev Anton,Freywald Tanya,Munhoz Erika Prando,Krishnan Anand,Ruppin Eytan,Lee Joo Sang,Rox Katharina,Toosi Behzad,Koebel Martin,Kinloch Mary,Hopkins Laura,Lee Cheng Han,Datla Raju,Yadav Sunil,Wu Yuliang,Baker Kristi,Empting Martin,Kiemer Alexandra K.,Freywald Andrew,Vizeacoumar Franco J.
Abstract
SummaryTumor heterogeneity poses a significant challenge in combating treatment resistance. Despite Polo-like kinase 1 (PLK1) being universally overexpressed in cancers and contributing to chromosomal instability (CIN), direct PLK1 inhibition hasn’t yielded clinical progress. To address this, we utilized the synthetic dosage lethality (SDL) approach, targeting PLK1’s genetic interactions for selective killing of overexpressed tumor cells while mitigating heterogeneity-associated challenges. Employing computational methods, we conducted a genome-wide shRNA screen, identifying 105 SDL candidates. Further in vivo CRISPR screening in a breast cancer xenograft model and in vitro CRISPR analysis validated these candidates. Employing Perturb-seq revealed IGF2BP2/IMP2 as a key SDL hit eliminating PLK1-overexpressing cells. Suppression of IGF2BP2, genetically or pharmacologically, downregulated PLK1 and limited tumor growth. Our findings strongly propose targeting PLK1’s genetic interactions as a promising therapeutic approach, holding broad implications across multiple cancers where PLK1 is overexpressed.
Publisher
Cold Spring Harbor Laboratory