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

ABSTRACT: The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer (TNBC), primarily by contributing to tumor cell survival and treatment resistance. However, the precise mechanisms remain unclear. In a model of local recurrence (LR), circulating tumor cells (CTC) engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1⁺-gene signature which was also identified in TNBC patients, suggesting ENPP1´s role in genome integrity. Blockade of ENPP1 using a permeable ENPP1 inhibitor (AVA-NP-695) reduced radioresistance, mechanistically attributed to decreased homologous recombination (HR) resulting in persistent DNA damage, as evidenced by enhanced tail moment and sustained γH2AX formation. T

SUBMITTER: Ruiz-Fernandez de Cordoba B 

PROVIDER: S-EPMC12162836 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature