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The Gurdon Institute

 
Figure 3 from Lloyd et al

Inhibitors of the protein kinase ATR (ATRi) are in clinical trials for the treatment of cancers. Studies from the Jackson lab now provide a comprehensive overview of genes that, when inactivated, enhance or diminish ATRi efficacy. They implicate Cyclin C and CDK8 in resistance mechanisms. This new knowledge could help in patient stratification and pre-empting drug resistance.

 

Loss of Cyclin C or CDK8 provides ATR inhibitor resistance by suppressing transcription-associated replication stress

Lloyd RL et al. (2021) Nucleic Acids Research, gkab628, DOI: 10.1093/nar/gkab628.

 

Abstract from the paper 

The protein kinase ATR plays pivotal roles in DNA repair, cell cycle checkpoint engagement and DNA replication. Consequently, ATR inhibitors (ATRi) are in clinical development for the treatment of cancers, including tumours harbouring mutations in the related kinase ATM. However, it still remains unclear which functions and pathways dominate long-term ATRi efficacy, and how these vary between clinically relevant genetic backgrounds. Elucidating common and genetic-background specific mechanisms of ATRi efficacy could therefore assist in patient stratification and pre-empting drug resistance. Here, we use CRISPR–Cas9 genome-wide screening in ATM-deficient and proficient mouse embryonic stem cells to interrogate cell fitness following treatment with the ATRi, ceralasertib.

We identify factors that enhance or suppress ATRi efficacy, with a subset of these requiring intact ATM signalling. Strikingly, two of the strongest resistance-gene hits in both ATM-proficient and ATM-deficient cells encode Cyclin C and CDK8: members of the CDK8 kinase module for the RNA polymerase II mediator complex. We show that Cyclin C/CDK8 loss reduces S-phase DNA:RNA hybrid formation, transcription-replication stress, and ultimately micronuclei formation induced by ATRi.

Overall, our work identifies novel biomarkers of ATRi efficacy in ATM-proficient and ATM-deficient cells, and highlights transcription-associated replication stress as a predominant driver of ATRi-induced cell death.

Illustration: excerpt from Fig 3 in the paper.

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Read more about research in the Jackson lab.

Watch Steve Jackson describe his research on DNA repair in this YouTube video