AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• DNA-dependent protein kinase (DNA-PK) is crucial for DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs).
• Targeting DNA-PK offers a potential strategy to enhance the efficacy of existing cancer therapies.

Purpose of the Study:

• To evaluate the efficacy of the DNA-PK inhibitor AZD7648 as a sensitizer in combination therapies for cancer treatment.
• To investigate the synergistic effects of AZD7648 with chemotherapy and PARP inhibitors in preclinical cancer models.

Main Methods:

• Utilized in vitro assays with ATM-deficient cells and in vivo xenograft and patient-derived xenograft (PDX) models.
• Administered AZD7648 in combination with radiation, doxorubicin, and the PARP inhibitor olaparib.
• Assessed tumor growth, regression, genomic instability, cell growth inhibition, and apoptosis.

Main Results:

• AZD7648 effectively sensitized tumors to radiation and doxorubicin, leading to sustained regressions in xenograft and PDX models.
• The combination of AZD7648 and olaparib significantly increased genomic instability, induced cell growth inhibition, and promoted apoptosis in ATM-deficient cells.
• AZD7648 demonstrated enhanced efficacy with olaparib across various doses and schedules, resulting in sustained tumor regression.

Conclusions:

• AZD7648 is a potent DNA-PK inhibitor that acts as an efficient sensitizer for DNA-damaging agents and PARP inhibitors.
• The combination of AZD7648 with other DDR-targeted agents holds significant promise for achieving deeper and more durable responses in cancer therapy.
• AZD7648 warrants clinical investigation as a novel therapeutic agent to complement existing cancer treatment strategies.