ATR inhibitors synergise with mitomycin C to enhance cytotoxicity in patient-derived non-muscle invasive bladder cancer organoids.

backgroundThere is a high recurrence rate in non-muscle invasive bladder cancer (NMIBC) patients treated with intravesical chemotherapy or BCG, indicating the need for novel treatment options. Synergy between DNA damage response inhibitors and chemotherapy has been shown for different solid tumours. Here, we explore whether combining chemotherapeutic agents with Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors is a suitable strategy to reduce recurrence in NMIBC.

methodsNMIBC patient-derived organoids (PDOs; n = 6) were exposed to mitomycin C (MMC) for 2 h, to mimic intravesical instillation, and subsequently to ATR inhibitors (berzosertib, ceralasertib, tuvusertib) for 72 h. Additionally, combination treatments with gemcitabine/epirubicin were analysed (n = 1 PDO). Cell viability and PDO regrowth potential were determined by microscopy and CellTiter-Glo luminescence assays 6 weeks post-treatment.

resultsPDO viability was severely impaired after combination treatment with chemotherapy and ATR inhibitors. This effect was maintained for 6 weeks after drug exposure. In contrast, PDOs treated with only chemotherapy or ATR inhibitors showed similar proliferation rates as untreated controls in week 6.

conclusionsThis study demonstrates synergy between ATR inhibitors and chemotherapy in NMIBC PDOs. Combining intravesical chemotherapy instillations with DNA damage response inhibitors should be further evaluated as a promising strategy to reduce recurrence rates for NMIBC.