Age-dependent chemotherapy response and vitamin D impact in paired patient-derived normal and tumor colorectal organoids

ABSTRACT Early-onset colorectal cancer (EO-CRC, <50 years) incidence is rising worldwide. Using paired patient-derived colorectal normal and tumor organoids, we demonstrate the therapeutic window of three standard chemotherapies. Normal organoids were more resistant than tumor organoids to 5-fluorouracil (5-FU) and oxaliplatin in both EO-CRC and late-onset CRC (LO-CRC) patients. However, for SN38, this therapeutic window was observed in LO-CRC but not in EO-CRC patients, revealing age-dependent differences in drug resistance. We also evaluated the effect of calcitriol, the active vitamin D metabolite with anti-CRC activity, on drug sensitivity. Calcitriol reduced the cytotoxicity of 5-FU and SN38 in normal organoids regardless of patient age, while it selectively decreased their cytotoxicity in EO-CRC but not in LO-CRC tumor organoids. This protective effect correlated with calcitriol antiproliferative action and transcriptional effects on drug-metabolism pathways. These findings identify clinically relevant age-dependent differences in chemotherapy response and support vitamin D-based strategies to design age-tailored precision treatments.