PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system
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Published:2023-07-03
Issue:1
Volume:7
Page:
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ISSN:2397-768X
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Container-title:npj Precision Oncology
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language:en
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Short-container-title:npj Precis. Onc.
Author:
Zimmer Kai, Kocher Florian, Untergasser Gerold, Kircher BrigitteORCID, Amann Arno, Baca Yasmine, Xiu Joanne, Korn W. MichealORCID, Berger Martin D., Lenz Heinz-JosefORCID, Puccini AlbertoORCID, Fontana Elisa, Shields Anthony F., Marshall John L., Hall Michael, El-Deiry Wafik S., Hsiehchen David, Macarulla Teresa, Tabernero JosepORCID, Pichler Renate, Khushman Moh’d, Manne Upender, Lou Emil, Wolf Dominik, Sokolova Viktorija, Schnaiter Simon, Zeimet Alain G., Gulhati Pat, Widmann Gerlig, Seeber AndreasORCID
Abstract
AbstractPolybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 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 PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 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., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821–1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-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 PBRM1-mut BTCs.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference45 articles.
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