Mechanistic models position ceritinib as a nuclear integrity disrupting therapy in pediatric liver tumors.

Background: Pediatric liver tumors with high-risk features pose therapeutic challenges, necessitating the development of more targeted and effective treatment strategies. Computational modeling of virtual patients and in silico drug response simulations, based on properly trained mechanistic models, is a powerful strategy to predict new treatment options. We aimed to leverage patient-specific mechanistic cell models to identify therapeutic alternatives for pediatric patients with high-risk liver tumors.

Methods: We generated digital twins of high-risk pediatric liver tumor patients by integrating clinical, genetic, and transcriptomic data and performed computational drug response simulations using mechanistic models. We validated the therapeutic potential of ceritinib in patient-derived xenograft models both in vitro and in vivo and used fluorescence microscopy-based imaging for functional analyses.

Results: Mechanistic models trained with digital twins of high-risk pediatric liver tumor patients identified ceritinib as the most effective treatment option through iterated in silico drug response simulations. Validation on a comprehensive drug-testing platform demonstrated that ceritinib, unlike other ALK receptor tyrosine kinase inhibitors with lower prediction scores, inhibited tumor growth by targeting non-canonical kinases. Mechanistically, ceritinib suppressed expression of nucleoporins, essential components of the nuclear pore complex overexpressed in pediatric liver tumors, consequently leading to the disruption of nuclear membrane integrity, perinuclear accumulation of mitochondria, production of reactive oxygen species, and induction of apoptosis. In patient-derived xenograft mouse models, ceritinib reduced tumor burden and extended survival by promoting cell death.

Conclusion: This study demonstrates the successful application of mechanistic models on virtual patients to position ceritinib as a promising therapeutic agent for high-risk pediatric liver tumors, highlighting its impact on key kinases implicated in tumor aggressiveness and its ability to compromise nuclear integrity.