Preclinical Drug-Response Profiling Identifies BMI1 Inhibition as a Therapeutic Option for Hepatoblastoma.
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Hepatoblastoma (HB), the most common pediatric liver cancer, exhibits marked variability in therapeutic response despite minimal genetic heterogeneity, implicating epigenetic regulation as a key driver of tumor behavior. Among these, polycomb repressor complexes (PRC) remain poorly explored as therapeutic targets. Integrative analysis of samples from patients with HB and public datasets identified BMI1, a core component of PRC1, as significantly upregulated, with high expression strongly associated with aggressive disease and poor survival. Functional screening of epigenetic inhibitors across 15 HB cell lines revealed BMI1 inhibition as the most effective therapeutic strategy, with strong concordance between in vitro predictions and in vivo responses in patient-derived xenograft (PDX) models. The BMI1 inhibitor PTC596 demonstrated the highest potency, consistently suppressing tumor growth across models. Mechanistically, PTC596 induced BMI1 degradation, reduced histone H2A ubiquitination, impaired microtubule dynamics, and restored intrinsic apoptosis by shifting the BCL2-BAX balance, leading to caspase-3/7 activation. Transcriptomic profiling confirmed apoptosis as the most significantly enriched pathway. In vivo, PTC596 markedly reduced tumor burden and proliferation while inducing pro-apoptotic signaling, without detectable toxicity. Together, these findings establish BMI1 as a critical oncogenic dependency in HB, demonstrate the value of robust preclinical tumor modeling for therapeutic validation, and identify PTC596 as a promising, mechanism-based treatment strategy.