Targeting DNA damage response deficiency in the treatment of breast cancer

Yizi JIN; Mingxi LIN; Jian ZHANG

doi:10.19401/j.cnki.1007-3639.2022.01.008

您当前的位置：

首页 >

文章列表页 >

Targeting DNA damage response deficiency in the treatment of breast cancer

Review | 更新时间：2025-12-31

- Targeting DNA damage response deficiency in the treatment of breast cancer
- China Oncology Vol. 32, Issue 1, Pages: 61-67(2022)
- 作者机构：
  
  复旦大学附属肿瘤医院Ⅰ期临床研究中心,复旦大学附属肿瘤医院肿瘤内科,复旦大学上海医学院肿瘤学系,上海 200032
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.01.008
  CLC： R737.9
- Received：12 May 2021，
  
  Revised：2021-08-05，
  
  Published：30 January 2022
- 稿件说明：
移动端阅览
Yizi JIN, Mingxi LIN, Jian ZHANG. Targeting DNA damage response deficiency in the treatment of breast cancer[J]. China Oncology, 2022, 32(1): 61-67.
DOI：

Yizi JIN, Mingxi LIN, Jian ZHANG. Targeting DNA damage response deficiency in the treatment of breast cancer[J]. China Oncology, 2022, 32(1): 61-67. DOI： 10.19401/j.cnki.1007-3639.2022.01.008.

摘要

DNA损伤应答（DNA damage response

DDR）缺陷是近年来乳腺癌治疗研究的热门靶点之一。DDR通路负责DNA损伤后的识别、信号转导和修复

其功能异常可导致细胞的凋亡或基因组不稳定性的增加。目前进入临床研究阶段的乳腺癌DDR靶向药物主要包括多聚腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase

PARP]抑制剂、ATM抑制剂、CHEK1抑制剂、ATR抑制剂及WEE1抑制剂等。主要从DDR缺陷的概念、以DDR作为靶点的基本原理、DDR各类靶向药物的临床研究现状及其在临床应用中的难点与挑战等方面展开综述。

Abstract

DNA damage response (DDR) deficiency has been one of the emerging targets in treating breast cancer in recent years. The DDR pathway is essential for the identification

signal transduction and repair of DNA damage. Its dysfunction may lead to cell apoptosis or genomic instability. Poly (ADP-ribose) polymerase (PARP) inhibitors

ATM inhibitors

CHEK1 inhibitors

ATR inhibitors and WEE1 inhibitors are DDR drugs that already in the clinical development for treating breast cancer. In this review

we introduced the concept of DDR deficiency

the rationale and research advances in DDR-targeted drugs

and discussed the challenges in its clinical applications.

关键词

Keywords

references

BRAY F , FERLAY J , SOERJOMATARAM I , et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J ] . CA Cancer J Clin , 2018 , 68 ( 6 ): 394 - 424 . DOI: 10.3322/caac.v68.6 http://doi.org/10.3322/caac.v68.6 http://doi.wiley.com/10.3322/caac.v68.6 http://doi.wiley.com/10.3322/caac.v68.6

JIANG Y Z , MA D , SUO C , et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies [J ] . Cancer Cell , 2019 , 35 ( 3 ): 428 - 440 . e5. DOI: 10.1016/j.ccell.2019.02.001 http://doi.org/10.1016/j.ccell.2019.02.001 https://linkinghub.elsevier.com/retrieve/pii/S1535610819300960 https://linkinghub.elsevier.com/retrieve/pii/S1535610819300960

BURSTEIN M D , TSIMELZON A , POAGE G M , et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer [J ] . Clin Cancer Res , 2015 , 21 ( 7 ): 1688 - 1698 . DOI: 10.1158/1078-0432.CCR-14-0432 http://doi.org/10.1158/1078-0432.CCR-14-0432 http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-14-0432 http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-14-0432

LEHMANN B D , BAUER J A , CHEN X , et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies [J ] . J Clin Invest , 2011 , 121 ( 7 ): 2750 - 2767 . DOI: 10.1172/JCI45014 http://doi.org/10.1172/JCI45014 http://www.jci.org/articles/view/45014 http://www.jci.org/articles/view/45014

KALIMUTHO M , PARSONS K , MITTAL D , et al. Targeted therapies for triple-negative breast cancer: combating a stubborn disease [J ] . Trends Pharmacol Sci , 2015 , 36 ( 12 ): 822 - 846 . DOI: 10.1016/j.tips.2015.08.009 http://doi.org/10.1016/j.tips.2015.08.009 https://linkinghub.elsevier.com/retrieve/pii/S0165614715001704 https://linkinghub.elsevier.com/retrieve/pii/S0165614715001704

Cancer Genome Atlas Network . Comprehensive molecular portraits of human breast tumours [J ] . Nature , 2012 , 490 ( 7418 ): 61 - 70 . DOI: 10.1038/nature11412 http://doi.org/10.1038/nature11412 https://doi.org/10.1038/nature11412 https://doi.org/10.1038/nature11412

STAAF J , GLODZIK D , BOSCH A , et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study [J ] . Nat Med , 2019 , 25 ( 10 ): 1526 - 1533 . DOI: 10.1038/s41591-019-0582-4 http://doi.org/10.1038/s41591-019-0582-4 https://doi.org/10.1038/s41591-019-0582-4 https://doi.org/10.1038/s41591-019-0582-4

HANAHAN D , WEINBERG R A . Hallmarks of cancer: the next generation [J ] . Cell , 2011 , 144 ( 5 ): 646 - 674 . DOI: 10.1016/j.cell.2011.02.013 http://doi.org/10.1016/j.cell.2011.02.013 https://linkinghub.elsevier.com/retrieve/pii/S0092867411001279 https://linkinghub.elsevier.com/retrieve/pii/S0092867411001279

KLINAKIS A , KARAGIANNIS D , RAMPIAS T . Targeting DNA repair in cancer: current state and novel approaches [J ] . Cell Mol Life Sci , 2020 , 77 ( 4 ): 677 - 703 . DOI: 10.1007/s00018-019-03299-8 http://doi.org/10.1007/s00018-019-03299-8 https://doi.org/10.1007/s00018-019-03299-8 https://doi.org/10.1007/s00018-019-03299-8

PEARL L H , SCHIERZ A C , WARD S E , et al. Therapeutic opportunities within the DNA damage response [J ] . Nat Rev Cancer , 2015 , 15 ( 3 ): 166 - 180 . DOI: 10.1038/nrc3891 http://doi.org/10.1038/nrc3891 https://doi.org/10.1038/nrc3891 https://doi.org/10.1038/nrc3891

FRIEDBERG E C . A brief history of the DNA repair field [J ] . Cell Res , 2008 , 18 ( 1 ): 3 - 7 . DOI: 10.1038/cr.2007.113 http://doi.org/10.1038/cr.2007.113 https://doi.org/10.1038/cr.2007.113 https://doi.org/10.1038/cr.2007.113

GOURLEY C , BALMAÑA J , LEDERMANN J A , et al. Moving from poly (ADP-ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy [J ] . J Clin Oncol , 2019 , 37 ( 25 ): 2257 - 2269 .

CHARTRON E , THEILLET C , GUIU S , et al. Targeting homologous repair deficiency in breast and ovarian cancers: biological pathways, preclinical and clinical data [J ] . Crit Rev Oncol Hematol , 2019 , 133 : 58 - 73 . DOI: 10.1016/j.critrevonc.2018.10.012 http://doi.org/10.1016/j.critrevonc.2018.10.012 https://linkinghub.elsevier.com/retrieve/pii/S1040842818301331 https://linkinghub.elsevier.com/retrieve/pii/S1040842818301331

LUCCHESI J C . Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanfgaster [J ] . Genetics , 1968 , 59 ( 1 ): 37 - 44 . DOI: 10.1093/genetics/59.1.37 http://doi.org/10.1093/genetics/59.1.37 https://academic.oup.com/genetics/article/59/1/37/5989040 https://academic.oup.com/genetics/article/59/1/37/5989040

DOBZHANSKY T . Genetics of natural populations; recombination and variability in populations of drosophila pseudoobscura [J ] . Genetics , 1946 , 31 : 269 - 290 .

PATEL A G , SARKARIA J N , KAUFMANN S H . Nonhomologous end joining drives poly (ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells [J ] . Proc Natl Acad Sci USA , 2011 , 108 ( 8 ): 3406 - 3411 . DOI: 10.1073/pnas.1013715108 http://doi.org/10.1073/pnas.1013715108 http://www.pnas.org/cgi/doi/10.1073/pnas.1013715108 http://www.pnas.org/cgi/doi/10.1073/pnas.1013715108

WILLIAMSON C T , KUBOTA E , HAMILL J D , et al. Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53 [J ] . EMBO Mol Med , 2012 , 4 ( 6 ): 515 - 527 . DOI: 10.1002/emmm.v4.6 http://doi.org/10.1002/emmm.v4.6 https://onlinelibrary.wiley.com/toc/17574684/4/6 https://onlinelibrary.wiley.com/toc/17574684/4/6

CECCALDI R , LIU J C , AMUNUGAMA R , et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair [J ] . Nature , 2015 , 518 ( 7538 ): 258 - 262 . DOI: 10.1038/nature14184 http://doi.org/10.1038/nature14184 https://doi.org/10.1038/nature14184 https://doi.org/10.1038/nature14184

MURAI J , HUANG S Y , DAS B B , et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors [J ] . Cancer Res , 2012 , 72 ( 21 ): 5588 - 5599 . DOI: 10.1158/0008-5472.CAN-12-2753 http://doi.org/10.1158/0008-5472.CAN-12-2753 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-12-2753 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-12-2753

MURAI J , ZHANG Y P , MORRIS J , et al. Rationale for poly (ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition [J ] . J Pharmacol Exp Ther , 2014 , 349 ( 3 ): 408 - 416 . DOI: 10.1124/jpet.113.210146 http://doi.org/10.1124/jpet.113.210146 http://jpet.aspetjournals.org/lookup/doi/10.1124/jpet.113.210146 http://jpet.aspetjournals.org/lookup/doi/10.1124/jpet.113.210146

KIM C , WANG X D , YU Y H . PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response [J ] . Elife , 2020 , 9 : e60637 . DOI: 10.7554/eLife.60637 http://doi.org/10.7554/eLife.60637 https://elifesciences.org/articles/60637 https://elifesciences.org/articles/60637

BAKR A , OING C , KÖCHER S , et al. Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation [J ] . Nucleic Acids Res , 2015 , 43 ( 6 ): 3154 - 3166 . DOI: 10.1093/nar/gkv160 http://doi.org/10.1093/nar/gkv160 http://academic.oup.com/nar/article/43/6/3154/2453440/Involvement-of-ATM-in-homologous-recombination http://academic.oup.com/nar/article/43/6/3154/2453440/Involvement-of-ATM-in-homologous-recombination

SALDIVAR J C , CORTEZ D , CIMPRICH K A . The essential kinase ATR: ensuring faithful duplication of a challenging genome [J ] . Nat Rev Mol Cell Biol , 2017 , 18 ( 10 ): 622 - 636 .

GHELLI LUSERNA DI RORÀ A , CERCHIONE C , MARTINELLI G , et al. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target [J ] . J Hematol Oncol , 2020 , 13 ( 1 ): 126 . DOI: 10.1186/s13045-020-00959-2 http://doi.org/10.1186/s13045-020-00959-2 https://doi.org/10.1186/s13045-020-00959-2 https://doi.org/10.1186/s13045-020-00959-2

YUE X Q , BAI C J , XIE D F , et al. DNA-PKcs: a multi-faceted player in DNA damage response [J ] . Front Genet , 2020 , 11 : 607428 . DOI: 10.3389/fgene.2020.607428 http://doi.org/10.3389/fgene.2020.607428 https://www.frontiersin.org/articles/10.3389/fgene.2020.607428/full https://www.frontiersin.org/articles/10.3389/fgene.2020.607428/full

WANG Z , SONG Y D , LI S B , et al. DNA polymerase θ (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse [J ] . J Biol Chem , 2019 , 294 ( 11 ): 3909 - 3919 . DOI: 10.1074/jbc.RA118.005188 http://doi.org/10.1074/jbc.RA118.005188 https://linkinghub.elsevier.com/retrieve/pii/S0021925820418058 https://linkinghub.elsevier.com/retrieve/pii/S0021925820418058

ROBSON M , IM S A , SENKUS E , et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation [J ] . N Engl J Med , 2017 , 377 ( 6 ): 523 - 533 . DOI: 10.1056/NEJMoa1706450 http://doi.org/10.1056/NEJMoa1706450 http://www.nejm.org/doi/10.1056/NEJMoa1706450 http://www.nejm.org/doi/10.1056/NEJMoa1706450

ROBSON M E , TUNG N , CONTE P , et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician & #x02019;s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer [J ] . Ann Oncol , 2019 , 30 ( 4 ): 558 - 566 . DOI: 10.1093/annonc/mdz012 http://doi.org/10.1093/annonc/mdz012 https://linkinghub.elsevier.com/retrieve/pii/S0923753419311111 https://linkinghub.elsevier.com/retrieve/pii/S0923753419311111

LITTON J K , RUGO H S , ETTL J , et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation [J ] . N Engl J Med , 2018 , 379 ( 8 ): 753 - 763 . DOI: 10.1056/NEJMoa1802905 http://doi.org/10.1056/NEJMoa1802905 http://www.nejm.org/doi/10.1056/NEJMoa1802905 http://www.nejm.org/doi/10.1056/NEJMoa1802905

TUNG N M , ROBSON M E , VENTZ S , et al. TBCRC 048: a phase Ⅱ study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (olaparib expanded) [J ] . J Clin Oncol , 2020 , 38 ( 15_suppl ): 1002 . DOI: 10.1200/JCO.2020.38.15_suppl.1002 http://doi.org/10.1200/JCO.2020.38.15_suppl.1002 https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.1002 https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.1002

FASCHING P A , LINK T , HAUKE J , et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study) [J ] . Ann Oncol , 2021 , 32 ( 1 ): 49 - 57 . DOI: 10.1016/j.annonc.2020.10.471 http://doi.org/10.1016/j.annonc.2020.10.471 https://linkinghub.elsevier.com/retrieve/pii/S0923753420429631 https://linkinghub.elsevier.com/retrieve/pii/S0923753420429631

LOIBL S , O'SHAUGHNESSY J , UNTCH M , et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial [J ] . Lancet Oncol , 2018 , 19 ( 4 ): 497 - 509 . DOI: 10.1016/S1470-2045(18)30111-6 http://doi.org/10.1016/S1470-2045(18)30111-6 https://linkinghub.elsevier.com/retrieve/pii/S1470204518301116 https://linkinghub.elsevier.com/retrieve/pii/S1470204518301116

EIKESDAL H P , YNDESTAD S , ELZAWAHRY A , et al. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer [J ] . Ann Oncol , 2021 , 32 ( 2 ): 240 - 249 . DOI: 10.1016/j.annonc.2020.11.009 http://doi.org/10.1016/j.annonc.2020.11.009 https://linkinghub.elsevier.com/retrieve/pii/S0923753420431643 https://linkinghub.elsevier.com/retrieve/pii/S0923753420431643

GATTI-MAYS M E , KARZAI F H , SOLTANI S N , et al. A phase & #x02161; single arm pilot study of the CHK1 inhibitor prexasertib (LY2606368) in BRCA wild-type, advanced triple-negative breast cancer [J ] . Oncologist , 2020 , 25 ( 12 ): e1013-e 1824 .

MATEO J , LORD C J , SERRA V , et al. A decade of clinical development of PARP inhibitors in perspective [J ] . Ann Oncol , 2019 , 30 ( 9 ): 1437 - 1447 . DOI: 10.1093/annonc/mdz192 http://doi.org/10.1093/annonc/mdz192 https://linkinghub.elsevier.com/retrieve/pii/S0923753419459851 https://linkinghub.elsevier.com/retrieve/pii/S0923753419459851

FEDERICI G , SODDU S . Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers [J ] . J Exp Clin Cancer Res , 2020 , 39 ( 1 ): 46 . DOI: 10.1186/s13046-020-01554-6 http://doi.org/10.1186/s13046-020-01554-6 https://doi.org/10.1186/s13046-020-01554-6 https://doi.org/10.1186/s13046-020-01554-6

BORG A , HAILE R W , MALONE K E , et al. Characterization of BRCA 1 and BRCA 2 deleterious mutations and variants of unknown clinical significan ce in unilateral and bilateral breast cancer: the WECARE study [J ] . Hum Mutat , 2010 , 31 ( 3 ): E1200-E1240 .

MILLOT G A , CARVALHO M A , CAPUTO S M , et al. A guide for functional analysis of BRCA 1 variants of uncertain significance [J ] . Hum Mutat , 2012 , 33 ( 11 ): 1526 - 1537 . DOI: 10.1002/humu.v33.11 http://doi.org/10.1002/humu.v33.11 http://doi.wiley.com/10.1002/humu.v33.11 http://doi.wiley.com/10.1002/humu.v33.11

TOLAND A E , ANDREASSEN P R . DNA repair-related functional assays for the classification of BRCA 1 and BRCA 2 variants: a critical review and needs assessment [J ] . J Med Genet , 2017 , 54 ( 11 ): 721 - 731 . DOI: 10.1136/jmedgenet-2017-104707 http://doi.org/10.1136/jmedgenet-2017-104707 https://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2017-104707 https://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2017-104707

ADZHUBEI I A , SCHMIDT S , PESHKIN L , et al. A method and server for predicting damaging missense mutations [J ] . Nat Methods , 2010 , 7 ( 4 ): 248 - 249 .

NG P C , HENIKOFF S . SIFT: predicting amino acid changes that affect protein function [J ] . Nucleic Acids Res , 2003 , 31 ( 13 ): 3812 - 3814 . DOI: 10.1093/nar/gkg509 http://doi.org/10.1093/nar/gkg509 https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkg509 https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkg509

FINDLAY G M , DAZA R M , MARTIN B , et al. Accurate classification of BRCA 1 variants with saturation genome editing [J ] . Nature , 2018 , 562 ( 7726 ): 217 - 222 . DOI: 10.1038/s41586-018-0461-z http://doi.org/10.1038/s41586-018-0461-z https://doi.org/10.1038/s41586-018-0461-z https://doi.org/10.1038/s41586-018-0461-z

Views

2004

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Guidelines for breast cancer diagnosis and treatment by China Anti-Cancer Association (2026 edition)

Guidelines for breast cancer diagnosis and treatment by China Anti-cancer Association (2024 edition)

Chinese consensus of cardio-oncology in breast cancer

New progress and prospect of breast cancer bone metastasis research from mechanism to clinic

Research progress of treatment and therapeutic target for Luminal B breast cancer

Related Author

The Society of Breast Cancer China Anti-Cancer Association

Breast Oncology Group of the Oncology Branch of the Chinese Medical Association

Breast Cancer China Anti-Cancer Association The Society of

of the Oncology Branch of the Chinese Medical Association Breast Oncology Group

Zan SHEN

Zhimin SHAO

Branch Cancer Support Rehabilitation Therapy Group of Chinese Medical Association Oncology

Treatment Consensus the Drafting Committee of China Breast Cancer Related Heart Disease Diagnosis and

Related Institution

Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University

Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University

上海交通大学附属第六人民医院肿瘤内科

上海交通大学附属第六人民医院普外科

Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

AI问答

⁰