DNA-PK Inhibition Shows Differential Radiosensitization in Orthotopic GBM PDX Models Based on DDR Pathway Deficits

Area of Science:

• Oncology
• Cancer Biology
• Radiotherapy

Background:

• Glioblastoma (GBM) is a highly therapy-resistant brain tumor with poor outcomes.
• Ionizing radiation (IR) is a standard GBM treatment, but local failures are common.
• DNA-dependent protein kinase inhibitors (DNA-PKi) are being investigated as radiosensitizers to improve GBM treatment efficacy.

Purpose of the Study:

• To investigate the radiosensitizing potential of the DNA-PKi peposertib in patient-derived glioblastoma xenografts.
• To explore the relationship between molecular features, pharmacokinetics, and peposertib's radiosensitizing efficacy.
• To identify predictive biomarkers for patient selection in DNA-PKi-based radiosensitization therapy.

Main Methods:

• Utilized orthotopic murine models with patient-derived glioblastoma xenografts (PDX).
• Assessed peposertib's radiosensitizing effects in vitro and in vivo, measuring DNA-PK inhibition and DNA damage repair markers (γH2AX foci).
• Analyzed the impact of TP53 mutation status on treatment response and DNA repair pathways (nonhomologous end joining and homologous recombination).

Main Results:

• Peposertib demonstrated radiosensitizing effects on GBM cells in vitro at concentrations ≥300 nmol/L, enhanced by prolonged post-IR exposure.
• In vivo, peposertib significantly increased survival in GBM120 xenografts but not in GBM10 xenografts, despite similar drug concentrations.
• Greater radiosensitization was associated with TP53 mutant GBM lines; introducing a dominant-negative TP53 mutant delayed tumor growth and impaired nonhomologous end joining.

Conclusions:

• Peposertib effectively inhibits DNA-PK and radiosensitizes GBM cells, but in vivo efficacy is variable.
• TP53 mutation status may serve as a predictive biomarker for response to peposertib-based radiosensitization.
• Further research is needed to elucidate the mechanisms behind discordant in vitro and in vivo responses and to optimize patient selection for DNA-PKi therapy.