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  11. Dual Enpp1/atm Depletion Blunts Dna Damage Repair Boosting Radioimmune Efficacy To Abrogate Triple-negative Breast Cancer

Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer

Borja Ruiz-Fernández de Córdoba1, Karmele Valencia1,2,3, Connor Welch1

  • 1Solid Tumors Program. Division of Oncology, Center for Applied Medical Research (CIMA)-University of Navarra, Pamplona, Spain.

Signal Transduction and Targeted Therapy
|June 12, 2025

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View abstract on PubMed

Summary
This summary is machine-generated.

Blocking ENPP1, an enzyme linked to triple-negative breast cancer (TNBC) recurrence, enhances radiation therapy by impairing DNA repair and boosting anti-tumor immunity. This strategy shows promise for treating TNBC metastasis and local recurrence.

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Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • The ectoenzyme ENPP1 is linked to triple-negative breast cancer (TNBC) metastasis and recurrence.
  • ENPP1's role in TNBC radioresistance and genome integrity is not fully understood.

Purpose of the Study:

  • To investigate the mechanisms by which ENPP1 contributes to TNBC radioresistance and recurrence.
  • To evaluate the therapeutic potential of ENPP1 inhibition in combination with other treatments.

Main Methods:

  • Utilized a local recurrence (LR) model and circulating tumor cells (CTCs) to study ENPP1's role.
  • Administered a permeable ENPP1 inhibitor (AVA-NP-695) and assessed DNA damage repair (DDR) pathways.
  • Conducted pharmacological screening for synergistic DDR inhibitors.
  • Performed in vivo studies with dual ENPP1/ATM inhibition and ionizing radiation (IR).

Main Results:

  • ENPP1 blockade reduced radioresistance by impairing homologous recombination (HR) and increasing DNA damage.
  • Dual ENPP1/ATM inhibition enhanced radiosensitivity and STING-TBK1 signaling.
  • Combined treatment led to significant tumor regression, reduced metastasis, and induced abscopal effects.
  • ENPP1 inhibition promoted robust innate and adaptive antitumor immune memory.

Conclusions:

  • ENPP1 is a critical mediator of genome integrity and immunosuppression in TNBC.
  • Targeting ENPP1 offers a promising strategy to overcome treatment resistance and control TNBC dissemination.
  • Combined ENPP1 inhibition with radiation and DDR inhibitors can enhance anti-tumor immunity and reduce recurrence.