<em><strong>PBRM1</strong></em><strong> mutations might render a subtype of biliary tract cancers sensitive to DDR targeting drugs </strong> <strong>Zimmer 2023, Data Table</strong>

<em>Polybromo-1</em> (<em>PBRM1</em>) loss-of-function mutations are present in a fraction of biliary tract cancers (BTCs). <em>PBRM1</em>, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of <em>PBRM1</em> mutated (mut) BTCs and to define potential translational aspects. 1,848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of <em>PBRM1</em> was performed in the BTC cell line EGI1 to assess therapeutic vulnerabilities of ATR and PARP inhibitors <em>in vitro</em>. <em>PBRM1</em> mutations were identified in 8.1% (n=150) of BTCs and were more prevalent in intrahepatic BTC (9.9%) compared to gallbladder cancer (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., <em>ARID1A 31% vs. 16%</em>) and DNA damage repair genes (e.g., <em>ATRX 4.4% vs. 0.3%</em>) were detected in <em>PBRM1</em>-mutated (mut) <em>vs.</em> <em>PBRM1</em>-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). <em>In vitro</em> experiments suggested that PARP +/- ATR inhibitors induce synthetic lethality in the <em>PBRM1</em> knockdown BTC model. Our findings served as scientific rationale for PARP inhibition in a heavily pretreated <em>PBRM1-</em>mut BTC patient, which induced disease control.This study represents the largest and most extensive molecular profiling study of <em>PBRM1-</em>mut BTCs, which <em>in vitro</em> sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as rationale for future testing of PARP/ATR inhibitors in <em>PBRM1-</em>mut BTCs.