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Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced

Jin-Na Zhang1,2, Meng-Meng Dong1,2, Wen Cao1

  • 1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

British Journal of Cancer
|June 14, 2024
PubMed
Abstract

Insights

Inhibiting DNA-PKcs enhances doxorubicin

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Targeting DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a potential strategy for multiple myeloma (MM) treatment.
  • Combining DNA damage-inducing agents with DNA-PKcs inhibitors may enhance chemotherapy by activating the cGAS-STING pathway.
  • The mechanism of cGAS release from chromatin and subsequent cytoplasmic translocation upon DNA damage remains unclear.

Purpose of the Study:

  • To investigate the role of DNA-PKcs inhibition in cGAS-STING-mediated chemosensitivity in MM.
  • To elucidate the mechanism by which DNA-PKcs inhibition activates the cGAS-STING pathway in MM cells.

Main Methods:

  • Mass spectrometry was employed to examine the effects of DNA-PKcs inhibition.
  • Mechanism studies were conducted to understand cGAS-STING pathway activation.
  • MM cells were treated with doxorubicin and DNA-PKcs inhibitors.

Main Results:

  • DNA-PKcs inhibition potentiated doxorubicin's anti-MM effect via cGAS-STING activation.
  • cGAS-STING activation led to MM cell death through the IRF3-NOXA-BAK axis and induced M1 macrophage polarization.
  • DNA-PKcs inhibition promoted cGAS release from cytoplasmic chromatin fragments, increasing cytosolic DNA and activating cGAS-STING.

Conclusions:

  • DNA-PKcs inhibition enhances doxorubicin efficacy in MM treatment.
  • This enhancement is achieved by releasing cGAS from damaged chromatin, thereby activating the cGAS-STING pathway.
  • The findings suggest a novel therapeutic approach for MM by targeting DNA repair mechanisms and immune activation.

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