Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up ~7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not amenable to curative therapy. Fo...

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Bibliographic Details
Published in:Cancers 2022-05, Vol.14 (10), p.2561
Main Authors: Yin, Chao, Kulasekaran, Monika, Roy, Tina, Decker, Brennan, Alexander, Sonja, Margolis, Mathew, Jha, Reena C, Kupfer, Gary M, He, Aiwu R
Format: Article
Language:English
Subjects:
Apoptosis
Biliary tract
Binding sites
Biomarkers
Cancer therapies
Cell cycle
Chemotherapy
Cytotoxicity
DNA damage
DNA repair
Drugs
FDA approval
Fibroblast growth factor receptors
Genes
Genotype & phenotype
Homologous recombination
Homologous recombination repair
Kinases
Lethality
Mutation
Ovarian cancer
Patients
Poly(ADP-ribose) polymerase
Review
Survival
Tumors
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Summary:Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up ~7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not amenable to curative therapy. For these patients, chemotherapy has been the mainstay treatment, providing an inadequate overall survival of less than one year. Despite the boom in targeted therapies over the past decade, only a few targeted agents have been approved in BTCs (i.e., IDH1 and FGFR inhibitors), perhaps in part due to its relatively low incidence. This review will explore current data on PARP inhibitors (PARPi) used in homologous recombination deficiency (HRD), particularly with respect to BTCs. Greater than 28% of BTC cases harbor mutations in genes involved in homologous recombination repair (HRR). We will summarize the mechanisms for PARPi and its role in synthetic lethality and describe select genes in the HRR pathway contributing to HRD. We will provide our rationale for expanding patient eligibility for PARPi use based on literature and anecdotal evidence pertaining to mutations in HRR genes, such as RAD51C, and the potential use of reliable surrogate markers of HRD.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14102561