Guiding ATR and PARP inhibitor combinations with chemogenomic screens

作者：Michal Zimmermann, Cynthia Bernier, Beatrice Kaiser, Sara Fournier, Li Li, Jessica Desjardins, Alexander M. Skeldon, Victoria M. Rimkunas, Artur Veloso, Jordan T.F. Young, Anne Roulston, Michael J. Zinda · 发表于：Cell Reports · 年份：2022 · DOI：10.1016/j.celrep.2022.111081 · 被引用次数：63 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、CRISPR and Genetic Engineering

Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations, or the "alternative lengthening of telomeres" telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. We present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.