Journal
CANCER RESEARCH
Volume 81, Issue 11, Pages 2888-2902Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-0628
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Funding
- Institut National de la Sante et de la RechercheMedicale (INSERM ATIP-Avenir Programme)
- Site de Recherche Integree sur le Cancer SOCRATE-2 [INCa-DGOS-INSERM_12551]
- Canceropole Ile-de-France [2017-1-EMERG-72]
- Association pour la Recherche contre le Cancer [PGA1 RF 20190208576]
- Cancer Research UK [C30061/A24439]
- Breast Cancer Now
- Fondation Bettencourt-Schueller
- Fondation des Treilles
- Canceropole Ile-De-France
- INSERM ITMO Cancer grant
- National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust
- Institute of Cancer Research, London
- Institut Servier
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Inactivation of PBRM1 is common in cancer, including ccRCC. Studies show that PARP and ATR inhibitors are synthetic lethal with PBRM1 deficiency, providing a basis for using these inhibitors in PBRM1-defective cancers.
Inactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. Significance: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer. [GRAPHICS] .
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