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

Cancers

Reena C. Jha¹  Gary M. Kupfer²  Mathew Margolis³  Brennan Decker³  Sonja Alexander³  Monika Kulasekaran⁴  Aiwu R. He⁴  Chao Yin⁴  Tina Roy⁴ 

[1] Department of Radiology, Georgetown University Medical Center, Washington, DC 20007, USA;Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA;Foundation Medicine, Cambridge, MA 20007, USA;Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA;

关键词: homologous recombination repair;    DNA damage repair;    PARP inhibitor;    biliary tract cancer;    synthetic lethality;   

DOI  :  10.3390/cancers14102561

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown