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Article Dans Une Revue Cancer Research Année : 2021

PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer

Roman Chabanon
Daphné Morel
  • Fonction : Auteur
Thomas Eychenne
  • Fonction : Auteur
Léo Colmet-Daage
  • Fonction : Auteur
Ilirjana Bajrami
  • Fonction : Auteur
Nicolas Dorvault
  • Fonction : Auteur
Marlène Garrido
  • Fonction : Auteur
Cornelia Meisenberg
  • Fonction : Auteur
Andrew Lamb
Carine Ngo
  • Fonction : Auteur
Suzanna Hopkins
Theodoros Roumeliotis
  • Fonction : Auteur
Samuel Jouny
Clémence Hénon
  • Fonction : Auteur
Asuka Kawai-Kawachi
  • Fonction : Auteur
Clémence Astier
  • Fonction : Auteur
Asha Konde
  • Fonction : Auteur
Elaine del Nery
  • Fonction : Auteur
Christophe Massard
Stephen Pettitt
Jyoti Choudhary
  • Fonction : Auteur
Geneviève Almouzni
Jean-Charles Soria
  • Fonction : Auteur
Eric Deutsch
Jessica Downs
  • Fonction : Auteur
Christopher Lord
Sophie Postel-Vinay

Résumé

Abstract 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.

Dates et versions

hal-03951734 , version 1 (23-01-2023)

Identifiants

Citer

Roman Chabanon, Daphné Morel, Thomas Eychenne, Léo Colmet-Daage, Ilirjana Bajrami, et al.. PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer. Cancer Research, 2021, 81 (11), pp.2888-2902. ⟨10.1158/0008-5472.CAN-21-0628⟩. ⟨hal-03951734⟩
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