Patient-derived organoids guide personalized therapy for KRAS-mutant pancreatic cancer: synergistic MEK/mTOR inhibition and predictive chemotherapy responses.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy driven by KRAS mutations in ~90% of cases, with high heterogeneity and limited efficacy of single targeted agents. Patient-derived organoids (PDOs) and xenografts (PDXs) offer promising platforms for personalized therapy by replicating tumor characteristics.

METHODS: We established a PDAC biobank with 69% PDO and 31% PDX success rates from 66 patient samples. Next-generation sequencing (NGS) of 425 oncogenes was performed, followed by 32-drugs in vitro screening in PDOs. The synergistic effects of the MEK inhibitor trametinib combined with the mTOR inhibitor AZD8055 or the pan-CDK inhibitor flavopiridol were evaluated in PDOs and validated in matched PDXs. We also validated PDOs in predicting clinical gemcitabine/paclitaxel (Gem/PTX) responses.

RESULTS: PDOs preserved tumor histological and genetic feature, with consistent drug responses across early and late passages. Trametini/AZD8055 exerted robust synergistic antitumor effects in all tested PDO and PDX models, while trametinib/flavopiridol failed in PDO/PDX-099. The Gem/PTX regimen achieved 75 -95% growth inhibition in PDOs, and the in vitro results were highly consistent with the in vivo efficacy in PDXs and the clinical CA19-9 remission of patients.

DISCUSSION: This study effectively integrated two preclinical models, PDOs and PDXs, both in vitro and in vivo, which are highly regarded in the fields of drug discovery and personalized medicine. The trametinib/AZD8055 combination is a promising precision therapeutic strategy, and PDOs can serve as a reliable tool to guide clinical therapy selection. Despite limitations such as small sample size, lack of tumor microenvironment and immune components in the model system, this work provides important preclinical evidence for the clinical translation of PDOs in the personalized therapy of PDAC.