Targeting Artemis Sensitizes B Cells to Topoisomerase 2 Poisons by Disrupting DNA-PKcs-Dependent Repair

TL;DR

Blocking Artemis with peposertib makes B cells more sensitive to Top2 poisons, suggesting a new cancer treatment strategy.

Contribution

Artemis inhibition with peposertib enhances Top2 poison efficacy in B cells, revealing a novel therapeutic approach.

Findings

Inhibiting DNA-PKcs with peposertib sensitizes B cells to Top2 poisons by blocking Artemis endonuclease activity.

Artemis loss leads to accumulation of Top2 DNA adducts, indicating a role beyond NHEJ in DNA repair.

High Artemis expression correlates with poor survival in cancers, highlighting its clinical relevance.

Abstract

Topoisomerase 2 (Top2) poisons are widely used in cancer therapy but are associated with toxicity and secondary malignancies. Removing Top2 adducts requires endonuclease activity and repair by non-homologous end joining (NHEJ). We show that the NHEJ enzyme Artemis is a promising target for co-treatment with Top2 poisons. Inhibition of the Artemis activator, DNA-PKcs, with peposertib (M3814) sensitizes B cells to Top2 poisons while ATM or ATR inhibition does not. Interestingly, while M3814 treatment blocks Artemis endonuclease activity, Artemis phosphorylation is still detectible and is only affected upon inhibiting ATM, suggestive of an additional role for Artemis in DNA damage response signaling. Additionally, Artemis loss results in a significant accumulation of Top2 DNA adducts following treatment, indicating Artemis may act outside its canonical role in NHEJ to reduce adduct burden. Clinical data demonstrates that high Artemis expression correlates with poor survival in several cancers, and we demonstrate that Artemis function is critical for survival following combination drug treatment. These insights can be leveraged to unlock new avenues for the treatment of aggressive cancers by enhancing the cytotoxicity of agents through blockade of DNA break repair.

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