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PBRM1 deficiency is synthetic lethal with PARP inhibitors in human cancers

ABSTRACT: Polybromo-1 (PBRM1), which encodes a specific subunit of the pBAF chromatin remodeling complex, is inactivated in multiple malignancies including 50% of clear cell renal cell carcinoma. At present, a therapeutic strategy that selectively targets PBRM1 defects does not exist. PBRM1 is involved in multiple cellular processes including transcription, replication and DNA repair. Using high-throughput screens and multiple isogenic and non-isogenic models, we found that PBRM1 defects cause synthetic lethality with several clinical PARP inhibitors, both in vitro and in vivo. This effect was enhanced using combinations with either small molecule ATR or BET inhibitors. Mechanistically, PBRM1 defects caused increased replication stress, R-loop formation and genomic instability that was exacerbated by PARP inhibitors. We also found that PARP and ATR inhibitors activate the cGAS-STING innate immunity pathway in PBRM1-deficient but not in PBRM1-proficient cells. These data provide the pre-clinical rationale for assessing PARP inhibitors as a monotherapy or in combination with ATR inhibitors or immune checkpoint inhibitors, in patients with PBRM1-deficient cancers.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Renal Clear Cell Carcinoma

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD017826 | Pride | 2022-02-21

REPOSITORIES: Pride

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