PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer

Area of Science:

• Oncology
• Cancer Biology
• Genetics

Background:

• Inactivation of Polybromo 1 (PBRM1), a PBAF chromatin remodeling complex subunit, is common in cancers like clear cell renal cell carcinoma (ccRCC).
• Targeting PBRM1-deficient cancers requires novel therapeutic strategies.

Purpose of the Study:

• To identify novel therapeutic targets for PBRM1-defective cancers.
• To investigate the synthetic lethality between PBRM1 deficiency and PARP/ATR inhibitors.

Main Methods:

• Utilized orthogonal functional genomic screens to identify drug sensitivities.
• Employed in vitro and in vivo models, including ccRCC xenografts.
• Performed quantitative mass spectrometry to analyze protein expression.
• Assessed R-loop resolution and innate immune signaling.

Main Results:

• Identified PARP and ATR inhibitors as synthetic lethal with PBRM1 deficiency.
• PBRM1-defective cells exhibit increased replication stress, micronuclei, and R-loops.
• Downregulation of R-loop processing factors observed in PBRM1-defective cells.
• PARP/ATR inhibitors induced cGAS/STING innate immune signaling.

Conclusions:

• PARP and ATR inhibitors are effective against PBRM1-defective cancers.
• Excessive R-loops contribute to synthetic lethality in PBRM1-deficient cells.
• Provides preclinical rationale for using PARP inhibitors in PBRM1-defective cancers.