2. Academic Validation
  3. RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer

RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer

  • Sci Adv. 2022 Feb 18;8(7):eabl9794. doi: 10.1126/sciadv.abl9794.
Chenkui Miao 1 2,  Takuya Tsujino 1 3,  Tomoaki Takai 1 3,  Fu Gui 1,  Takeshi Tsutsumi 1 3,  Zsofia Sztupinszki 4,  Zengjun Wang 2,  Haruhito Azuma 3,  Zoltan Szallasi 4,  Kent W Mouw 5,  Lee Zou 6,  Adam S Kibel 1,  Li Jia 1
Affiliations

Affiliations

  • 1 Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 3 Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
  • 4 Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
  • 5 Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
PMID: 35179959 DOI: 10.1126/sciadv.abl9794
Abstract

Current targeted Cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate Cancer individually or jointly. Loss of RNASEH2B confers Cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 resensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic test to determine who may benefit from PARP inhibition. Last, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP Inhibitor resistance caused by RB1 loss.

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