Pancreatic cancer organoid-screening captures personalized sensitivity and chemoresistance suppression upon cytochrome P450 3A5-targeted inhibition.

Cytochrome P450 3A5 (CYP3A5) has been proposed as a predictor of therapy response in subtypes of pancreatic ductal adenocarcinoma cancer (PDAC). To validate CYP3A5 as a therapeutic target, we developed a high-content image organoid-based screen to quantify the phenotypic responses to the selective inhibition of CYP3A5 enzymatic activity by clobetasol propionate (CBZ), using a cohort of PDAC-derived organoids (PDACOs). The chemoresistance of PDACOs to a panel of standard-of-care drugs, alone or in combination with CBZ, was investigated. PDACO pharmaco-profiling revealed CBZ to have anti-cancer activity that was dependent on the CYP3A5 level. In addition, CBZ restored chemo-vulnerability to cisplatin in a subset of PDACOs. A correlative proteomic analysis established that CBZ caused the suppression of multiple cancer pathways sustained by or associated with a mutant form of p53. Limiting the active pool of CYP3A5 enables targeted and personalized therapy to suppress pro-oncogenic mechanisms that fuel chemoresistance in some PDAC tumors.