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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg.
Cancer research. 2021 Apr 22 [Epub ahead of print]
Roman M Chabanon, Daphné Morel, Thomas Eychenne, Léo Colmet-Daage, Ilirjana Bajrami, Nicolas Dorvault, Marlène Garrido, Cornelia Meisenberg, Andrew Lamb, Carine Ngo, Suzanna R Hopkins, Theodoros I Roumeliotis, Samuel Jouny, Clémence Hénon, Asuka Kawai-Kawachi, Clémence Astier, Asha Konde, Elaine Del Nery, Christophe Massard, Stephen J Pettitt, Raphaël Margueron, Jyoti S Choudhary, Geneviève Almouzni, Jean-Charles Soria, Eric Deutsch, Jessica A Downs, Christopher J Lord, Sophie Postel-Vinay
ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France., The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom., Epigenetics and Genome Stability Team, The Institute of Cancer Research, London, United Kingdom., Sage Bionetworks, Seattle, Washington., Functional Proteomics Team, The Institute of Cancer Research, London, United Kingdom., Institut Curie, PSL Research University, Department of Translational Research, The Biophenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, France., Drug Development Department, DITEP, Gustave Roussy, Villejuif, France., Institut Curie, PSL Research University, INSERM Unit U934, CNRS UMR 3215, Paris, France., Institut Curie, PSL Research University, CNRS, UMR 3664, Equipe Labellisée Ligue contre le Cancer, Paris, France., Université Paris Saclay, Université Paris-Sud, Faculté de Médicine, Le Kremlin Bicêtre, France., The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. ., ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33888468