POLQ and DNA-PK inhibition in muscle-invasive bladder cancer : Enhancing radiosensitivity with novel DNA damage response inhibitors to improve radiotherapy outcomes

BACKGROUND: Muscle-invasive bladder cancer (MIBC) includes histological subtypes such as urothelial carcinoma (UC) and the rarer, prognostically unfavorable, squamous cell carcinoma (SCC). Standard treatment is radical cystectomy, while alternatives like chemotherapy or radiotherapy are particularly limited in SCC. Radiosensitizers, such as DNA-dependent protein kinase (DNA-PK) and DNA polymerase theta (POLQ) inhibitors, could selectively enhance radiotherapy effects in tumor cells and represent promising approaches for clinical translation. OBJECTIVE: This study analyzed the radiosensitizing effects of DNA-PK and POLQ inhibition ex vivo in patient-derived MIBC cell lines of UC and SCC subtypes. MATERIALS AND METHODS: The DNA-PK inhibitor AZD7648 (DNA-PKi) and the POLQ inhibitor ART558 (POLQi) were tested ex vivo in patient-derived SCC (p-SCC; n = 3) and UC (p-UC; n = 3) cell cultures. Effects were assessed in combination with ionizing radiation (IR) using XTT cell viability assays (IC50), clonogenic survival assays,

• Pannhausen, J.
• Chughtai, A. A.
• Melzer, M. K.
• Ma, Y.
• Wirtz, J.
• Kleger, A.
• Saar, M.
• Eble, M. J.
• Jonigk, D. D.
• Rose, M.
• Gaisa, N. T.