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

Abstract

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 <i>TCF4</i> 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.