Longevity & AgingBAP1 Loss Makes Liver Cancers Vulnerable to CDK4/6 Inhibitors
Researchers used genome-wide CRISPR screening combined with transcriptomic, epigenomic, and proteomic profiling to identify BAP1 as a synthetic-lethal partner with CDK4/6 inhibitors in hepatobiliary cancers. Under sustained CDK4/6 inhibition, the deubiquitinase BAP1 removes the H2AK119ub histone mark at the TCF4 promoter, activating WNT and EMT signaling to push tumor cells into a stem-like, drug-tolerant state. Blocking BAP1 genetically or pharmacologically dramatically improved the efficacy of abemaciclib in multiple mouse tumor models and patient-derived organoids. These findings expose an epigenetic escape route cancer cells exploit to survive CDK4/6 inhibitor therapy and nominate BAP1 inhibition as a clinically actionable combination strategy.
