Organoid-based drug screening identifies homoharringtonine as a therapeutic agent for anaplastic thyroid cancer via TFEB-mediated lysosomal dysfunction.

PURPOSE: Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy with unmet clinical needs for novel therapeutic agents. Most prior studies have relied on limited ATC cell lines, which fail to recapitulate tumor heterogeneity. This study aimed to discover novel agent for ATC via patient-derived organoid (PDO)-based drug screening and investigate the underlying therapeutic mechanism.

METHODS: Drug screening was performed on ATC organoids using a drug library of stem cell differentiation compounds. RNA-sequencing identified pathway-level mechanisms, while structure-based molecular docking prioritized target proteins.

RESULTS: Using a library of stem cell differentiation compounds, we identified homoharringtonine (HHT) as a potent inhibitor for ATC growth in vitro and in vivo. Mechanistically, this effect was mediated by lysosomal dysfunction, which blocked autophagosome-lysosome fusion and triggered cytotoxicity. Furthermore, HHT exhibited high affinity for the PI3K p110 subunit, activating the PI3K-AKT-mTOR pathway to phosphorylate transcription factor EB, retaining it in the cytoplasm and thereby inhibiting lysosomal biogenesis.

CONCLUSION: Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.