Genome-wide screenings identify BAP1 as a synthetic-lethality target with CDK4/6 inhibitors.

The nongenetic mechanisms by which cancer cells escape cell cycle inhibition remain inadequately understood. Here, we uncover an epigenetic pathway driving adaptive resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hepatobiliary cancers using integrative approach combining genome-wide CRISPR screenings with transcriptional, epigenetic, and proteomic profiling. Sustained CDK4/6 inhibition triggers BAP1-dependent chromatin remodeling that induces a stem cell-like epigenetic state. Specifically, BAP1 removes ubiquitin modification (H2AK119ub) at the TCF4 promoter, activating WNT and EMT signaling to enhance cellular plasticity and survival under therapy. Notably, genetic and pharmacologic inhibition of BAP1 markedly improves abemaciclib efficacy in multiple mouse models and patient-derived organoids (PDOs). These findings establish BAP1 as a key regulator of tumor plasticity and adaptive resistance through epigenetic reprogramming and suggest a promising strategy for overcoming adaptive therapeutic CDK4/6i resistance by targeting quiescent, drug-resistant cancer cells.