Combatting cancer by exploiting the DNA Damage Response

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What happens in the DNA Damage Response?

DNA损伤反应(DNA Damage Response, DDR)是目前肿瘤学临床研究的重点之一. 澳门葡京赌博游戏对DDR在癌症中的作用的理解使澳门葡京赌博游戏能够进一步推动澳门葡京赌博游戏的研究，以更广泛的癌症为目标，包括难以治疗或侵袭性癌症.1

由于暴露于内部或外部DNA损伤剂(如紫外线)，每天都会发生DNA损伤, ionising radiation and chemotherapeutic agents)1,2 DDR描述了检测和修复DNA损伤的多种方式. One key factor influences the DDR – the type of DNA damage.1 虽然某些类型的DNA损伤可以快速修复，但复杂的DNA损伤需要更长的时间来修复.3 在这种情况下，通路被激活以暂停细胞周期，并为修复留出时间.

Importantly, most cancers have a greater dependency on the DDR, 由于在癌症发展过程中失去了一种或多种DDR能力.1 By understanding and identifying these dependencies, 澳门葡京赌博游戏可以使用精准医学方法和靶向DDR抑制剂来最大化DNA损伤并选择性地杀死癌细胞. 这为癌症治疗提供了一种真正有针对性的方法，有可能改善多种肿瘤类型的患者预后.1

正是通过澳门葡京赌博游戏针对DDR机制的科学驱动方法，澳门葡京赌博游戏能够为肿瘤学精准医学的进步做出贡献.

Our commitment to DDR in oncology

With our industry-leading portfolio and research targeting DDR mechanisms, 澳门葡京赌博游戏正在追求澳门葡京赌博游戏的雄心壮志，希望有一天能够消除癌症这一致死原因.

Basing our approach on using ground-breaking science, 澳门葡京赌博游戏继续进一步了解靶向治疗，以实现切实的患者利益. 澳门葡京赌博游戏正在努力不断推进澳门葡京赌博游戏对DDR在癌症中的作用的了解，并推动靶向DDR疗法的发展，以实现精准医疗. To achieve this, 澳门葡京赌博游戏需要能够识别和测试哪些患者具有表明潜在DDR缺陷的遗传生物标志物, to allow patients to be matched to the right treatment.

澳门葡京赌博游戏的肿瘤产品线继续为多种肿瘤类型的患者提供潜在的生物标志物选择治疗策略，包括 ovarian, breast, prostate and pancreatic cancers. 澳门葡京赌博游戏还使用一系列技术和探索性终点来开发检测方法，以告知患者选择和监测患者复发, 目的是找到进一步开发新的靶向治疗方法的机会. 澳门葡京赌博游戏致力于突破科学的界限，利用澳门葡京赌博游戏的DDR目标，为全球患者实现尽可能好的结果.

Susan Galbraith

Executive Vice-President, Oncology R&D, AstraZeneca
Mark O'Connor

Chief Scientist, Early Oncology Discovery, AstraZeneca

The gateway to oncology

癌症治疗的方法已经从传统的化疗和放疗方案过渡到更加个性化和有针对性的方法. As expected with personalised medicine, there are different biomarkers that can be utilised, and this adds to the level of personalisation that can be achieved. 近年来，澳门葡京赌博游戏看到了令人钦佩的进步，特别是在卵巢方面, breast, 前列腺癌和胰腺癌——包括并扩展基于BRCA1/2基因的患者选择, 它们参与了被称为同源重组修复的DDR途径, 将重点转移到更广泛的适应症，卵巢癌和前列腺癌定义为同源重组缺陷.1,4,5 澳门葡京赌博游戏很自豪地把注意力集中在DDR上，开创了靶向治疗的新时代, continuing to contribute to the value of precision medicine.

到目前为止，澳门葡京赌博游戏已经在DDR研究方面取得了开创性的进展，并将继续推动澳门葡京赌博游戏在癌症治疗这一重要领域的知识边界. 此外，澳门葡京赌博游戏致力于应对新出现的耐药性，并实现更持久的应对措施. Central to this, 澳门葡京赌博游戏正在探索DDR抑制剂组合的效果，包括那些与其他靶向治疗的组合.

Understanding DDR pathways 

了解DDR通路和相关蛋白使澳门葡京赌博游戏能够靶向肿瘤特异性DDR依赖性，优先杀死癌细胞.

Normal cell

Normal cell

Tens of thousands of DNA damage events take place in human cells every day.6  To repair these DNA damage events and enable cells to function normally, a series of processes takes place, collectively known as the DNA Damage Response (DDR).1 If left unrepaired, DNA损伤的水平可能累积到致命的水平，并导致细胞死亡.1

DNA damage

DDR is dependent on the type of DNA damage

许多蛋白质参与不同的修复途径，包括但不限于:

  • PARP1 and PARP2 – 聚[adp -核糖]聚合酶是参与多种细胞过程的酶，包括DNA单链断裂修复(SSBR)。, 与碱基切除修复(BER)中使用的蛋白质和复合物重叠的途径7
  • ATM – a protein kinase 通过同源重组修复(HRR)或非同源末端连接(NHEJ)参与DNA双链断裂(DSB)修复1,8
  • DNA-PK – 这种DNA依赖性蛋白激酶在NHEJ途径修复DNA DSB中起关键作用9
  • BRCA1 and BRCA2 – these genes encode proteins that are key in the repair of DNA DSB by HRR, and are tumour suppressor proteins1

Value of HRR and HRD

The value of HRR and HRD

同源重组修复(HRR)途径缺陷的细胞准确修复DNA双链断裂的能力降低.9

HRR基因突变(HRRm)代表HRR基因的任何突变，导致该蛋白的功能丧失或完全丧失, such as to BRCA1/2 and ATM. 这使得修复途径无效，并可能导致基因组不稳定和癌细胞的发展.1,10,11,12

同源重组缺乏症(Homologous Recombination Deficiency, HRD)是用来描述一条功能性HRR通路缺失的术语. HRRm can therefore lead to HRD.13

HRD is observed across a number of different tumour types and in some, for example ovarian cancer, can be highly enriched. In these HRD tumour types, 抑制PARP1可导致基因组不稳定性的积累并导致癌细胞死亡.14

Genetic mutations in cancers

Exploiting HRD and genetic mutations in cancers

DDR targeted therapy, such as PARP inhibitors, 是否可以通过阻断PARP1酶活性来利用癌细胞中的同源重组缺陷(HRD),1 preventing DNA single-strand break repair and trapping PARP1 onto the DNA. 在复制细胞中，这可能导致DNA双链断裂，而这种断裂通常会通过HRR途径修复. In HRD tumours, for example those with BRCA1/2 loss of function mutations, PARP抑制剂治疗可导致无法承受的基因组不稳定性和癌细胞死亡.15,16 Normal cells, which retain HRR capability, 不受这种方式的影响-使其成为真正有针对性的癌症治疗方法.15,16

Cell cycle

The DDR is influenced by the cell cycle

DNA replication stress

DNA replication is essential for cells to proliferate. 任何干扰正常DNA复制的东西都被称为“DNA复制压力”. Cancers have much higher levels of replication stress than normal cells. DDR的一个重要方面是涉及ATR等蛋白质的复制应激反应(RSR), WEE1 and DNA-PK.17,18

  • ATR 是一种关键的蛋白激酶，通过各种方式，负责调节RSR. In addition, 它起着关键的细胞周期检查点作用，并通过HRR促进DNA双链断裂修复16
  • WEE1 一种蛋白酪氨酸激酶在调节细胞周期进程中起双重作用吗, through S-phase and at the G2/M checkpoint. WEE1 is a key RSR protein19
  • DNA-PK is a protein kinase with a role in NHEJ. In addition, it has been linked to the RSR

Cell division

For a tumour to grow, cell division must occur.

  • Aurora B 是一种在细胞分裂过程中协助DNA染色体排列的蛋白激酶吗. 它的抑制作用要么导致子细胞之间染色体分裂不均匀，要么导致细胞分裂失败, leading to cell death20,21
  • Aurora B 是否在肝癌、结肠癌、乳腺癌、肾癌、肺癌和甲状腺癌中过度表达. 抑制极光B激酶有可能增加有丝分裂应激，因此与其他DDR药物联合使用22

这些DDR蛋白一起确保细胞周期不会随着受损的DNA而进行. 因此，DNA修复和细胞周期检查点调节因子内在地相互联系.

Applying the science to achieve tangible targeted therapy benefits in oncology

 

Exploit HRD to induce cancer cell death through our DDR portfolio

继续探索联合治疗，在临床中获得更广泛和更持久的反应

Pioneer the use of DDR inhibitors to exploit replication stress in cancers

The power of combinations

Looking beyond DDR inhibitor monotherapy and led by our pre-clinical science, 澳门葡京赌博游戏有广泛的临床试验，正在调查以ddr为基础的联合治疗的效果. DDR therapies can be combined, to achieve better outcomes, 将治疗扩展到预期对DDR单药治疗有反应的患者之外，并在临床中克服耐药性.23

澳门葡京赌博游戏还研究了DDR和免疫肿瘤学(IO)药物联合使用的效果. The inhibition of DDR pathways may prime an anti-tumour immune response, 这意味着针对DDR和免疫反应途径的联合治疗可能会改善结果.24  澳门葡京赌博游戏的肿瘤学产品线跨越不同的科学重点平台，使澳门葡京赌博游戏能够解决一些最常见到最危及生命和罕见的癌症，并超越最初的反应，着眼于长期结果和治疗, eventually, a potential cure.

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References

1. Alhmoud J, et al. DNA Damage/Repair Management in Cancers. Cancers (Basel). 2020 Apr; 12(4): 1050.

2. Li L, et al. DNA Repair Pathways in Cancer Therapy and Resistance. Front. Pharmacol.2021.

3. Vitor A, et al. Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox. Front. Mol. Biosci. 2021.

4. Krzyszczyk P, et al. The growing role of precision and personalized medicine for cancer treatment. Technology (Singap World Sci). 2018 Sep-Dec; 6(3-4): 79–100.

5. Wong W, et al. 胰腺癌中的BRCA突变:谱、当前管理、挑战和未来展望. Cancer Manag Res. 2020; 12: 2731–2742.

6. Verma N, et al. DNA Damage Stress: Cui Prodest? Int J Mol Sci. 2019 Mar; 20(5): 1073.

7. Ronson GE, et al. PARP1和PARP2通过依赖fbh1的Rad51调控稳定碱基切除修复中间体上的复制叉. Nat Commun. 2018 Feb 21;9(1):746.

8. Balmus G, et al. ATM协调dna损伤反应，以对抗断裂复制分叉处的毒性非同源末端连接. Nat Commun. 2019; 10: 87.

9. Mohiuddin and Kang. DNA-PK as an Emerging Therapeutic Target in Cancer. Frontiers in Oncology. 2019;9(635).

10. Keung M, et al. PARP抑制剂作为治疗乳腺癌同源重组缺乏症的药物. Journal of clinical medicine. 2019;8(4), pp.435.

11. Norquist B, et al. 同源重组基因突变与gog218卵巢癌患者预后:NRG肿瘤/妇科肿瘤组研究. Clin Cancer Res. 2018 Feb 15; 24(4): 777–783.

12. Pawlyn C, et al. 作为多发性骨髓瘤同源修复缺陷标志的杂合性缺失:PARP抑制的作用? Leukemia. 2018;32, pp.1561–1566.

13. Heeke A, et al. 同源重组相关基因突变在多种癌症类型中的流行. JCO Precis Oncol. 2018;2018:PO.17.00286.

14. da Cunha Colombo Bonadio R, et al. 卵巢癌同源重组缺乏症的流行病学及治疗进展. Clinics (Sao Paulo, Brazil). 2018;73(suppl 1), e450s.

15. Chaudhuri and Nussenzweig. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nature Reviews Molecular Cell Biology. 2017;18(10):610-621.

16. Rose M, et al. PARP抑制剂:临床相关性、作用机制和肿瘤耐药. Front Cell Dev Biol. 2020 Sep 9;8:564601.

17. Forment and O’Connor. Targeting the replication stress response in cancer. Pharmacology & Therapeutics. 2018;188:155-167.

18. Ubhi and Brown. Exploiting DNA Replication Stress for Cancer Treatment. Cancer Res. 2018;2018:PO.17.00286.

19. Moiseeva T, et al. WEE1激酶抑制剂AZD1775在未受干扰的G1期和s期细胞中诱导CDK1激酶依赖性起源放电. PNAS. 2019;116(48):23891-23893.

20. McVey S, et al. 着丝点中的极光B张力传感机制确保染色体准确分离. Int J Mol Sci. 2021 Aug; 22(16): 8818.

21. Luserna di Rora A, et al. 急性白血病有丝分裂死亡和有丝分裂滑脱之间的平衡:一个新的治疗窗口? Journal of Hematology & Oncology. 2019;12:123.

22. Du R, et al. 靶向AURKA在癌症中的作用:肿瘤治疗的分子机制和机遇. Molecular Cancer. 2021;20(15).

23. Pilie P, et al. PARP Inhibitors: Extending Benefit Beyond BRCA Mutant Cancers. Clin Cancer Res. 2019 Jul 1;25(13):3759-3771.

24. Samstein R, et al. The DNA damage response in immunotherapy and Radiation. Advances in Radiation Oncology. 2018:3;527-533.

Veeva ID: Z4-51061
Date of preparation: December 2022