Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas.

Patients with advanced soft-tissue sarcomas (STS) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase (DNA-PK) catalytic subunit is a multifunctional serine-threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining. To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacologic inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacologic inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma. ©2023 American Association for Cancer Research.

Citation

Audrey Laroche-Clary, Coralie Josensi, Marie-Alix Derieppe, Sarah Belhomme, Véronique Vendrely, Raul Perret, Elaine Cadogan, Antoine Italiano. Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas. Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Feb 01;30(3):629-637

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PMID: 37982819

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