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Defining BRCA replication dysfunction in therapy response

定义治疗反应中的 BRCA 复制功能障碍

基本信息

批准号：
10412057
负责人：
Sharon B Cantor
金额：
$ 54.48万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-12 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412057
关键词：
Ants BRCA deficient BRCA1 gene BRCA2 gene Biological Models Breast Cancer gene Cancer Patient Cells Chemoresistance Complex DNA DNA Double Strand Break DNA Repair DNA biosynthesis DNA replication fork Data Set Defect Degradation Pathway Development Double Strand Break Repair Filament Functional disorder Genes Genome Goals Grant Hereditary Breast Carcinoma Human Cell Line Hypersensitivity Kinetics Knowledge Malignant Neoplasms Maps Measures Mediating Modeling Molecular Mutagens Mutation Outcome Pathway interactions Patients Pharmaceutical Preparations Platinum Polymerase Proteins Proteomics Research Resistance Resistance development Ribose Sampling Single-Stranded DNA Source Stress Testing Transact Tumor Markers cancer cell chemotherapy effective therapy experimental study homologous recombination inhibitor insight mutant patient response predictive marker prevent protein function resistance mechanism response restraint therapy resistant tissue culture treatment response tumor

项目摘要

The goal of this grant is to harness a new understanding of vulnerabilities in tumors with mutations in the hereditary breast cancer genes. We have found that cells deficient in the BRCA-pathway genes, fail to properly respond to DNA replication perturbations (stress) and consequently replication is not restrained properly and ssDNA regions (gaps) develop. We find that when gaps are present, BRCA cancer cells are sensitive to therapy and when gaps are avoided, resistance occurs. Our findings that gaps are fundamental to therapy response is a paradigm shift in the current framework that proposes that persistent DNA breaks and fork degradation is the cause of sensitivity. Thus, we propose to employ state-of-the-art experiments to map the molecular determinants of this BRCA pathway fork restraint function. Moreover, will identify the gap making machinery that is critical for therapy response and the gap avoidance machinery that is critical to therapy resistance. Lastly, we will re- examine models of therapy resistance previously attributed to restored DNA repair and fork protection and determine if gap suppression is instead the fundamental resistance mechanism. Collectively, these proposed studies will identify how cancer cells succumb to and eventually gain resistance to chemotherapy and provide valuable insight towards biomarkers predicting resistance and drugs that prevent resistance.

这笔赠款的目标是利用对肿瘤易感性的新理解，这些肿瘤的基因突变遗传性乳腺癌基因。我们已经发现，缺乏BRCA途径基因的细胞，不能正确地对DNA复制扰动(应激)作出反应，因此复制没有得到适当的抑制单链DNA区域(缺口)形成。我们发现，当存在缺口时，BRCA癌细胞对治疗敏感当差距被避免时，就会产生阻力。我们的研究发现，差距是治疗反应的根本当前框架中提出持续DNA断裂和分叉降解的范式转变是因为敏感。因此，我们建议使用最先进的实验来绘制分子决定因素图这种BRCA通路的分叉抑制功能。此外，将确定对以下方面至关重要的缝隙形成机制治疗反应和缺口避免机制，这是治疗抵抗的关键。最后，我们将重新- 检查以前归因于恢复的DNA修复和分叉保护和确定间隙抑制是否为基本阻力机制。总的来说，这些建议研究将确定癌细胞如何屈服于化疗并最终获得抗药性，并提供对预测耐药性的生物标记物和预防耐药性的药物的有价值的见解。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exploiting replication gaps for cancer therapy.

DOI：
10.1016/j.molcel.2022.04.023
发表时间：
2022-07-07
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Cong, Ke;Cantor, Sharon B.
通讯作者：
Cantor, Sharon B.

Comprehensive Mutational Analysis of the BRCA1-Associated DNA Helicase and Tumor-Suppressor FANCJ/BACH1/BRIP1.

DOI：
10.1158/1541-7786.mcr-20-0828
发表时间：
2021-06
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Calvo JA;Fritchman B;Hernandez D;Persky NS;Johannessen CM;Piccioni F;Kelch BA;Cantor SB
通讯作者：
Cantor SB

Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.

DOI：
10.1016/j.molcel.2021.09.005
发表时间：
2021-11-18
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Dias, Mariana Paes;Tripathi, Vivek;van der Heijden, Ingrid;Cong, Ke;Manolika, Eleni-Maria;Bhin, Jinhyuk;Gogola, Ewa;Galanos, Panagiotis;Annunziato, Stefano;Lieftink, Cor;Andujar-Sanchez, Miguel;Chakrabarty, Sanjiban;Smith, Graeme C. M.;van de Ven, Marieke;Beijersbergen, Roderick L.;Bartkova, Jirina;Rottenberg, Sven;Cantor, Sharon;Bartek, Jiri;Chaudhuri, Arnab Ray;Jonkers, Jos
通讯作者：
Jonkers, Jos

Revisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer".