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

Nicholas Pannunzio1,2, Melissa Folkerts1,2, Cameron Hom1,2

  • 1Divison of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA.

Research Square
|June 30, 2025
PubMed

Insights

Targeting the Artemis enzyme with DNA-PKcs inhibitors like peposertib can enhance cancer therapy by sensitizing cells to Topoisomerase 2 (Top2) poisons. This approach may reduce toxicity and improve outcomes in aggressive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • DNA Repair

Background:

  • Topoisomerase 2 (Top2) poisons are crucial cancer therapeutics but cause toxicity and secondary malignancies.
  • Repair of Top2-induced DNA damage involves endonuclease activity and non-homologous end joining (NHEJ).
  • Artemis is a key enzyme in NHEJ, implicated in repairing DNA double-strand breaks.

Purpose of the Study:

  • To investigate Artemis as a therapeutic target for co-treatment with Top2 poisons.
  • To evaluate the efficacy of inhibiting Artemis activators, specifically DNA-PKcs, in sensitizing cancer cells to Top2 poisons.
  • To explore Artemis's role beyond NHEJ in DNA damage response signaling and adduct removal.

Main Methods:

  • Inhibition of DNA-PKcs with peposertib (M3814) in B cells treated with Top2 poisons.
  • Assessment of Artemis endonuclease activity and phosphorylation status upon inhibition of DNA-PKcs, ATM, or ATR.
  • Analysis of Top2 DNA adduct accumulation in Artemis-deficient cells.
  • Correlation of Artemis expression with patient survival data in various cancers.

Main Results:

  • Inhibition of DNA-PKcs with peposertib sensitized B cells to Top2 poisons; ATM or ATR inhibition did not.
  • Peposertib blocked Artemis endonuclease activity, but phosphorylation persisted without ATM inhibition, suggesting additional signaling roles.
  • Artemis deficiency led to increased Top2 DNA adducts, indicating a role in adduct burden reduction.
  • High Artemis expression correlated with poor survival in several cancers, and its function was critical for survival under combination treatment.

Conclusions:

  • Artemis is a promising target for combination therapy with Top2 poisons, enhancing their efficacy.
  • Inhibiting DNA-PKcs with peposertib offers a strategy to sensitize cancer cells to Top2 poisons.
  • Artemis plays a multifaceted role in DNA damage response and repair, impacting Top2 adducts and overall cancer cell survival.
Keywords:
ATMArtemisB cellDNA repairDNA-PKcsNHEJpeposertib (M3814)topoisomerase poison

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