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

Area of Science:

• Oncology
• Epigenetics
• Cancer Biology

Background:

• Nongenetic mechanisms of cancer cell adaptation to cell cycle inhibitors are not fully understood.
• Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are used in cancer therapy, but resistance can develop.
• Understanding adaptive resistance is crucial for improving treatment outcomes.

Purpose of the Study:

• To identify epigenetic pathways driving adaptive resistance to CDK4/6 inhibitors in hepatobiliary cancers.
• To elucidate the role of BAP1 in mediating this resistance mechanism.
• To explore therapeutic strategies targeting BAP1 to overcome resistance.

Main Methods:

• Integrative approach combining genome-wide CRISPR screening with transcriptional, epigenetic, and proteomic profiling.
• Analysis of BAP1-dependent chromatin remodeling and its effect on gene expression.
• Evaluation of BAP1 inhibition in preclinical models (mouse models and patient-derived organoids).

Main Results:

• Sustained CDK4/6 inhibition induces BAP1-dependent chromatin remodeling, leading to a stem cell-like epigenetic state.
• BAP1 activates WNT and EMT signaling by removing H2AK119ub at the TCF4 promoter, enhancing cancer cell plasticity and survival.
• Inhibition of BAP1 significantly improves the efficacy of abemaciclib in preclinical models.

Conclusions:

• BAP1 is a key regulator of tumor plasticity and adaptive resistance via epigenetic reprogramming.
• Targeting BAP1 represents a promising strategy to overcome adaptive resistance to CDK4/6 inhibitors.
• This approach may be effective in treating quiescent, drug-resistant cancer cells.