Ceritinib inhibits growth and ACTH production of PitNETs: Insights from patient-derived organoids.

ACTH-secreting pituitary neuroendocrine tumors (PitNETs), also known as Cushing's disease (CD), are a rare condition lacking effective pharmacological treatments. Drug development for CD has been limited by the absence of suitable preclinical research models. Here, we established a patient-derived organoid (PDO) model and used it for screening tyrosine kinase inhibitors for CD. Ceritinib emerged as a promising therapeutic candidate due to its potent and consistent efficacy across PDOs from different patients in vitro, as well as in vivo in a xenograft mouse model. Multi-omics analyses and molecular validation revealed that Ceritinib exerts its effects by inhibiting phosphorylation within the PI3K-Akt signaling pathway. Specifically, Akt1 was identified as a key mediator, as its knockdown attenuated the suppressive potency of Ceritinib on both tumor growth and ACTH synthesis. Furthermore, Akt1-mediated regulation of ACTH was found to occur via Nur77, the transcriptional activator of POMC. In conclusion, Ceritinib effectively suppresses tumor growth and ACTH production in PDOs of both functioning and silent CD, positioning it as a promising therapeutic agent for CD.