Pharmaco-genomic characterization of pancreatic and biliary tract cancer tumoroids for drug response

Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) are highly aggressive malignancies with limited therapeutic options. In this study, we established eleven tumoroids with paired patient-derived xenograft (PDX) models (five PDAC and six BTC), enabling scalable <i>in vitro</i> drug screening and corresponding <i>in vivo</i> validation. These tumoroids retained the histological and genetic characteristics of their original tumors and exhibited varied responses to chemotherapeutic agents. Drug screening identified PI3Kα inhibitors as promising candidates for both PDAC and BTC tumoroids, which was further validated in matched PDX models. Moreover, we uncovered genetic alterations and transcriptomic signatures associated with different drug sensitivities. Notably, combining a G9a degrader (G9D-4) with the KRAS^G12D inhibitor MRTX1133 elicited synergistic anti-tumor effects in KRAS^G12D-mutant tumoroids. Overall, our study provides preclinical insights from a small PDAC and BTC tumoroid cohort, supporting tumoroid-based platforms for exploratory drug screening and pharmacogenomic analyses and suggesting potential therapeutic directions that warrant further validation.