Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?
Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?
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胆道癌中的同源重组修复：PARP抑制剂的主要靶点？
DOI：
10.3390/cancers14102561
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发表时间：
2022-05-23
期刊：
影响因子：
5.2
通讯作者：
He, Aiwu R.
中科院分区：
文献类型：
--
作者：
Yin, Chao;Kulasekaran, Monika;Roy, Tina;Decker, Brennan;Alexander, Sonja;Margolis, Mathew;Jha, Reena C.;Kupfer, Gary M.;He, Aiwu R.
关键词：
胆道癌（btc）是一种罕见但致命的胃肠道肿瘤，通常在疾病的晚期被诊断出来。尽管有大量研究调查了btc的最佳全身治疗方案，但目前的化疗方案在总生存率方面只提供了适度的益处。同源重组修复（HRR）作为更广泛的DNA损伤修复（DDR）系统的一部分的快速发展的研究使得利用PARP抑制剂（PARPi）等靶向药物来利用这一途径的缺陷成为可能。我们将回顾使用PARPi的基本原理，以及进一步释放其在处理BTC方面的潜力的考虑。胆道癌（btc）是一种异质性的恶性肿瘤，约占所有胃肠道肿瘤的7%。它具有明显的侵袭性，难以治疗；事实上，大约70%的BTC患者被诊断为晚期，无法切除，无法接受根治性治疗。对于这些患者，化疗一直是主要的治疗方法，总生存期不足一年。尽管靶向治疗在过去十年中蓬勃发展，但只有少数靶向药物被批准用于btc（即IDH1和FGFR抑制剂），部分原因可能是其发病率相对较低。本综述将探讨用于同源重组缺陷（HRD）的PARP抑制剂（PARPi）的当前数据，特别是关于btc。超过28%的BTC病例携带同源重组修复（HRR）相关基因突变。我们将总结PARPi的机制及其在合成致死性中的作用，并描述HRR通路中与HRD相关的一些基因。我们将根据与HRR基因突变（如RAD51C）有关的文献和轶事证据，以及可靠的HRD替代标记物的潜在使用，为扩大患者使用PARPi的资格提供依据。
Biliary tract cancers (BTCs) are a rare but deadly group of gastrointestinal tumors that are often diagnosed in the advanced stages of disease. Despite large studies investigating optimal systemic therapy options in BTCs, current chemotherapies provide only modest benefits in overall survival. The rapidly evolving study of homologous recombination repair (HRR) as part of the broader DNA damage repair (DDR) system makes it possible to exploit deficiencies in this pathway with targeted agents such as PARP inhibitors (PARPi). We will review the rationale for PARPi use, as well as considerations for further unlocking their potential in treating BTC. 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.
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影响因子：
8.8
作者：
Farshidfar F;Zheng S;Gingras MC;Newton Y;Shih J;Robertson AG;Hinoue T;Hoadley KA;Gibb EA;Roszik J;Covington KR;Wu CC;Shinbrot E;Stransky N;Hegde A;Yang JD;Reznik E;Sadeghi S;Pedamallu CS;Ojesina AI;Hess JM;Auman JT;Rhie SK;Bowlby R;Borad MJ;Cancer Genome Atlas Network;Zhu AX;Stuart JM;Sander C;Akbani R;Cherniack AD;Deshpande V;Mounajjed T;Foo WC;Torbenson MS;Kleiner DE;Laird PW;Wheeler DA;McRee AJ;Bathe OF;Andersen JB;Bardeesy N;Roberts LR;Kwong LN
通讯作者：
Kwong LN
影响因子：
76.2
作者：
Fennell, Dean A.;King, Amy;Thomas, Anne
通讯作者：
Thomas, Anne
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
DOI：
10.1016/s1470-2045(20)30109-1
发表时间：
2020-05
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Abou-Alfa GK;Sahai V;Hollebecque A;Vaccaro G;Melisi D;Al-Rajabi R;Paulson AS;Borad MJ;Gallinson D;Murphy AG;Oh DY;Dotan E;Catenacci DV;Van Cutsem E;Ji T;Lihou CF;Zhen H;Féliz L;Vogel A
通讯作者：
Vogel A
影响因子：
8.8
作者：
Choi YE;Meghani K;Brault ME;Leclerc L;He YJ;Day TA;Elias KM;Drapkin R;Weinstock DM;Dao F;Shih KK;Matulonis U;Levine DA;Konstantinopoulos PA;Chowdhury D
通讯作者：
Chowdhury D