Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Zimmermann, M.; Bernier, C.; Kaiser, B.; Fournier, S.; Li, L.; Desjardin, J.; Skeldon, A.; Rimkunkas, V.; Veloso, A.; Young, J. T.; Roulston, A.; Zinda, M.

doi:10.1101/2021.12.13.472393

bioRxiv · 10.1101/2021.12.13.472393

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Zimmermann, M.·Bernier, C.·Kaiser, B.·Fournier, S.·Li, L.·Desjardin, J.·Skeldon, A.·Rimkunkas, V.·Veloso, A.·Young, J. T.·Roulston, A.·Zinda, M.

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Abstract

Combinations of inhibitors of Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases (PARPi) 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. Altogether, we present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.

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Zimmermann, M., Bernier, C., Kaiser, B., Fournier, S., Li, L., Desjardin, J., Skeldon, A., Rimkunkas, V., Veloso, A., Young, J. T., Roulston, A., Zinda, M.. 2021-12-14. Guiding ATR and PARP inhibitor combinations with chemogenomic screens. https://doi.org/10.1101/2021.12.13.472393

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