DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFβ/PD-L1 Targeted...

Area of Science:

• Oncology
• Radiation Oncology
• Cancer Immunology

Background:

• Radiotherapy is a cornerstone of cancer treatment, but enhancing its efficacy and safety remains critical.
• DNA-dependent protein kinase (DNA-PK) inhibitors, like peposertib, block the repair of radiation-induced DNA double-strand breaks (DSB).
• Cancer cells lacking p53 are uniquely sensitive to DNA-PK inhibition due to compromised cell-cycle checkpoints.

Purpose of the Study:

• To investigate the potential of peposertib in combination with radiotherapy and immunotherapy for improved cancer treatment.
• To evaluate the impact of DNA-PK inhibition on DNA repair, cell death, and inflammatory signaling in irradiated cancer cells.
• To assess the efficacy of a triple combination therapy involving radiation, peposertib, and a TGFβ/PD-L1 inhibitor.

Main Methods:

• Utilized peposertib, a selective DNA-PK inhibitor, in preclinical cancer models.
• Examined the effects of peposertib on the repair of radiation-induced DSBs.
• Assessed the impact of peposertib on cell-cycle progression, chromosome segregation, and micronuclei formation in p53-deficient cancer cells.
• Evaluated the combined effects of radiation, peposertib, and bintrafusp alfa (a TGFβ/PD-L1 inhibitor) on tumor regression and inflammatory signaling.

Main Results:

• Peposertib effectively inhibited the repair of radiation-induced DSBs, leading to enhanced cancer cell killing, especially in p53-deficient cells.
• Inhibition of DNA-PK promoted chromosome misalignment and missegregation, accelerating micronuclei formation and activating cGAS/STING inflammatory signaling.
• Peposertib treatment elevated PD-L1 expression in irradiated cancer cells.
• The triple combination of radiation, peposertib, and bintrafusp alfa demonstrated superior efficacy compared to dual combinations.

Conclusions:

• Inhibiting DNA-PK with peposertib enhances radiotherapy by increasing cancer cell death and improving response to TGFβ/PD-L1 targeted immunotherapy.
• The combination therapy promotes inflammatory signaling and PD-L1 expression, offering a novel strategy for radioimmunotherapy.
• This approach holds promise for the effective treatment of locally advanced solid tumors, particularly those with p53 deficiency.