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PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system
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Journal Article
PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system
2023
Overview
Polybromo-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.
