BAP1 Loss Makes Liver Cancers Vulnerable to CDK4/6 Inhibitors

CDK4/6 inhibitors like abemaciclib are approved for breast cancer and under investigation in many other tumor types, but adaptive resistance—where cancer cells escape cell-cycle arrest without acquiring new mutations—remains a major barrier. The mechanisms underlying this nongenetic escape are poorly understood, motivating the search for combination targets that prevent or reverse it.

To systematically identify genes whose loss sensitizes cancer cells to CDK4/6 inhibition, the authors performed genome-wide CRISPR knockout screens in hepatobiliary cancer cell lines treated with abemaciclib. BAP1 (BRCA1-associated protein-1), a nuclear deubiquitinase and bona fide tumor suppressor, emerged as a top synthetic-lethal hit across multiple screens. BAP1 is commonly mutated in cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma, making it an immediately clinically relevant target.

Mechanistic studies revealed that sustained CDK4/6 inhibitor exposure induces BAP1-dependent chromatin remodeling. BAP1 enzymatically removes the repressive histone mark H2AK119 monoubiquitination (H2AK119ub) at the promoter of TCF4, a master transcriptional activator of WNT target genes. This derepression activates both WNT signaling and epithelial-to-mesenchymal transition (EMT), driving tumor cells into a stem cell-like state characterized by enhanced plasticity and survival under therapy. In this way, BAP1 acts as an epigenetic switch that translates drug pressure into a heritable, drug-tolerant cell identity—without any genetic mutation.

Validation experiments showed that BAP1 genetic knockout or pharmacologic inhibition markedly enhanced the anti-tumor activity of abemaciclib in multiple complementary model systems: cell lines, syngeneic and xenograft mouse tumor models, and patient-derived organoids (PDOs) from hepatobiliary cancer patients. The combination suppressed tumor growth beyond either agent alone and abrogated the emergence of the resistant stem-like phenotype, confirming on-target activity.

These findings reframe BAP1 not merely as a passive tumor suppressor but as an active driver of adaptive therapeutic resistance through epigenetic reprogramming. Because BAP1 is frequently lost by mutation in several cancer types, its absence could itself be exploited as a biomarker predicting heightened CDK4/6 inhibitor sensitivity. Conversely, in tumors retaining wild-type BAP1, pharmacologic BAP1 inhibition combined with CDK4/6 inhibitors may prevent the emergence of resistance. Caveats include the predominantly hepatobiliary cancer focus of the experimental models, and translation to other tumor contexts and ultimately clinical trials will be needed.