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Zimmer, Kai; Kocher, Florian; Untergasser, Gerold; Kircher, Brigitte; Amann, Arno; Baca, Yasmine; Xiu, Joanne; Korn, W. Micheal; Berger, Martin D.; Lenz, Heinz-Josef; Puccini, Alberto; Fontana, Elisa; Shields, Anthony F.; Marshall, John L.; Hall, Michael; El-Deiry, Wafik S.; Hsiehchen, David; Macarulla, Teresa; Tabernero, Josep; Pichler, Renate; Khushman, Moh’d; Manne, Upender; Lou, Emil; Wolf, Dominik; [...]

PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

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  • Media type: E-Article
  • Title: PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system
  • Contributor: Zimmer, Kai; Kocher, Florian; Untergasser, Gerold; Kircher, Brigitte; Amann, Arno; Baca, Yasmine; Xiu, Joanne; Korn, W. Micheal; Berger, Martin D.; Lenz, Heinz-Josef; Puccini, Alberto; Fontana, Elisa; Shields, Anthony F.; Marshall, John L.; Hall, Michael; El-Deiry, Wafik S.; Hsiehchen, David; Macarulla, Teresa; Tabernero, Josep; Pichler, Renate; Khushman, Moh’d; Manne, Upender; Lou, Emil; Wolf, Dominik; [...]
  • imprint: Springer Science and Business Media LLC, 2023
  • Published in: npj Precision Oncology
  • Language: English
  • DOI: 10.1038/s41698-023-00409-5
  • ISSN: 2397-768X
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p><jats:italic>Polybromo-1</jats:italic> (<jats:italic>PBRM1</jats:italic>) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). <jats:italic>PBRM1</jats:italic>, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of <jats:italic>PBRM1</jats:italic> mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of <jats:italic>PBRM1</jats:italic> was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. <jats:italic>PBRM1</jats:italic> mutations were identified in 8.1% (<jats:italic>n</jats:italic> = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., <jats:italic>ARID1A</jats:italic> 31% vs. 16%) and DNA damage repair genes (e.g., <jats:italic>ATRX</jats:italic> 4.4% vs. 0.3%) were detected in <jats:italic>PBRM1</jats:italic>-mutated (mut) vs. <jats:italic>PBRM1</jats:italic>-wildtype (wt) BTCs. No difference in real-world overall survival was observed between <jats:italic>PBRM1</jats:italic>-mut and <jats:italic>PBRM1</jats:italic>-wt patients (HR 1.043, 95% CI 0.821–1.325, <jats:italic>p</jats:italic> = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the <jats:italic>PBRM1</jats:italic> knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated <jats:italic>PBRM1-</jats:italic>mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of <jats:italic>PBRM1-</jats:italic>mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in <jats:italic>PBRM1-</jats:italic>mut BTCs.</jats:p>
  • Access State: Open Access