Combatting cancer by exploiting the DNA Damage Response

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What happens in the DNA Damage Response?

The DNA Damage Response (DDR) is one of the scientific mechanisms we are focusing on to improve the clinical paradigm in oncology. Our understanding of the role the DDR plays in cancer is enabling us to push our research further to target a broad range of cancers including difficult to treat or aggressive cancers.1

Damage to DNA occurs on a daily basis due to exposure to internal or external DNA damaging agents (such as UV light, ionising radiation and chemotherapeutic agents)1,2 and the DDR describes the multiple ways in which DNA damage is detected and repaired. One key factor influences the DDR – the type of DNA damage.1 While some types of DNA damage are repaired quickly, complex DNA damage takes longer to repair.3 In this scenario, pathways are activated to pause the cell cycle and allow time for repair.

Importantly, most cancers have a greater dependency on the DDR, due to the loss of one or more DDR capabilities during the development of cancer.1 By understanding and identifying these dependencies, we can use precision medicine approaches and targeted DDR inhibitors to maximise DNA damage and selectively kill cancer cells. This provides a truly targeted approach to cancer treatment with the potential to improve patient outcomes across multiple tumour types.1

It is through our science-driven approach in targeting DDR mechanisms that we have been able to contribute to advances in precision medicine in oncology.

Our commitment to DDR in oncology

With our industry-leading portfolio and research targeting DDR mechanisms, we are pursuing our bold ambition to one day eliminate cancer as a cause of death.

Basing our approach on using ground-breaking science, we continue to further our understanding of targeted therapy with the aim of achieving a tangible patient benefit. We are working hard to continually advance what we know about the role of DDR in cancer and drive the development of targeted DDR therapies to enable precision medicine. To achieve this, we need to be able to identify and test which patients have genetic biomarkers indicating underlying DDR defects, to allow patients to be matched to the right treatment.

Our oncology pipeline continues to deliver potential biomarker-selected treatment strategies for patients across multiple tumour types including ovarian, breast, prostate and pancreatic cancers. We are also using a range of technologies and exploratory endpoints to both develop assays to inform patient selection and monitor patient relapse, with the aim of identifying further opportunities for developing new targeted therapies. We are committed to pushing the boundaries of science and harnessing our DDR targets to achieve the best possible outcomes for patients worldwide.

Susan Galbraith

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

Chief Scientist, Early Oncology Discovery, AstraZeneca

The gateway to oncology

Approaches to cancer treatment have transitioned from the conventional chemotherapy and radiotherapy options to a more personalised and targeted approach. 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. We have seen admirable advancements in recent years – particularly in ovarian, breast, prostate and pancreatic cancers – to both include and expand beyond patient selection based on BRCA1/2 genes, which are involved in a DDR pathway known as Homologous Recombination Repair, shifting focus to a broader indication in ovarian cancer and prostate cancer defined as Homologous Recombination Deficiency.1,4,5 We are proud to focus our attention on DDR and usher in a new era of targeted therapy, continuing to contribute to the value of precision medicine.

We have come so far in pioneering DDR research and will continue to push the boundaries of our knowledge in this important area of cancer therapy. In addition, we are committed to tackling emerging resistance and achieving more durable responses. Central to this, we are exploring the effects of DDR inhibitor combinations including those with other targeted therapies.

Understanding DDR pathways 

Understanding DDR pathways and the proteins involved allows us to target tumour-specific DDR dependencies to preferentially kill cancer cells.

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, the level of DNA damage may accumulate to a lethal level and result in cell death.1

DNA damage

DDR is dependent on the type of DNA damage

Many proteins are involved in the different repair pathways including but not limited to:

  • PARP1 and PARP2 – poly [ADP-ribose] polymerases are enzymes involved in various cellular processes including DNA single-strand break repair (SSBR), a pathway which overlaps with proteins and complexes used in Base Excision Repair (BER)7
  • ATM – a protein kinase involved in DNA double-strand break (DSB) repair by Homologous Recombination Repair (HRR) or Non-Homologous End Joining (NHEJ)1,8
  • DNA-PK – this DNA-dependent protein kinase is critical in DNA DSB repair by the NHEJ pathway9
  • 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

Cells with deficiencies in Homologous Recombination Repair (HRR) pathways have reduced capacity to accurately repair DNA double-strand breaks.9

HRR gene mutations (HRRm) represent any mutation to an HRR gene that results in the loss-of-function or complete loss of the protein, such as to BRCA1/2 and ATM. This renders the repair pathway ineffective and can contribute to genomic instability and cancer cell development.1,10,11,12

Homologous Recombination Deficiency (HRD) is the term used to describe the loss of a functional HRR pathway. 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, inhibition of PARP1 can lead to an accumulation of genomic instability and result in cancer cell death.14

Genetic mutations in cancers

Exploiting HRD and genetic mutations in cancers

DDR targeted therapy, such as PARP inhibitors, can exploit Homologous Recombination Deficiency (HRD) in cancer cells by blocking PARP1 enzyme activity,1 preventing DNA single-strand break repair and trapping PARP1 onto the DNA. In replicating cells this can lead to DNA double-strand breaks that would normally be repaired through the HRR pathway. In HRD tumours, for example those with BRCA1/2 loss of function mutations, PARP inhibitor therapy can result in an unsupportable level of genomic instability and cancer cell death.15,16 Normal cells, which retain HRR capability, are not affected in this way – making this a truly targeted approach to cancer treatment.15,16

Cell cycle

The DDR is influenced by the cell cycle

DNA replication stress

DNA replication is essential for cells to proliferate. Anything that interferes with normal DNA replication is known as ‘DNA replication stress’. Cancers have much higher levels of replication stress than normal cells. An important aspect of the DDR is the Replication Stress Response (RSR) that involves proteins such as ATR, WEE1 and DNA-PK.17,18

  • ATR is a key protein kinase which, through various ways, is responsible for regulating the RSR. In addition, it plays key cell cycle checkpoint roles and facilitates DNA double strand break repair via HRR16
  • WEE1 is a protein tyrosine kinase that plays dual roles in regulating cell cycle progression, 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 is a protein kinase which assists in DNA chromosome alignment during cell division. Its inhibition causes either unequal splitting of the chromosomes between the daughter cells or failure of the cell to divide, leading to cell death20,21
  • Aurora B is known to be over-expressed in liver, colon, breast, renal, lung and thyroid cancers. Inhibition of Aurora B kinase has the potential to increase mitotic stress and therefore be combined with other DDR agents22

Together these DDR proteins ensure the cell cycle does not progress with compromised DNA. As such, DNA repair and cell cycle checkpoint regulators are inherently interlinked.

Applying the science to achieve tangible targeted therapy benefits in oncology

 

Exploit HRD to induce cancer cell death through our DDR portfolio

Continue to explore combination therapies to achieve broader and more durable responses in the clinic

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, we have a broad range of clinical trials that are investigating the effects of DDR-based combination treatments. DDR therapies can be combined, to achieve better outcomes, to extend therapies beyond patients who are expected to respond to DDR monotherapy and to overcome resistance in the clinic.23

We also look at the effects of combining DDR and Immuno-Oncology (IO) agents. The inhibition of DDR pathways may prime an anti-tumour immune response, meaning combination therapies that target DDR and immune response pathways could result in improved outcomes.24  The diversity of our oncology pipeline spanning different scientific platforms of focus allows us to address some of the most common to the most life threatening and rare cancers and look beyond initial response to long-term outcomes and, 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. BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects. 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 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation. Nat Commun. 2018 Feb 21;9(1):746.

8. Balmus G, et al. ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks. 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 Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers. Journal of clinical medicine. 2019;8(4), pp.435.

11. Norquist B, et al. Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group Study. Clin Cancer Res. 2018 Feb 15; 24(4): 777–783.

12. Pawlyn C, et al. Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition? Leukemia. 2018;32, pp.1561–1566.

13. Heeke A, et al. Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types. JCO Precis Oncol. 2018;2018:PO.17.00286.

14. da Cunha Colombo Bonadio R, et al. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. 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 Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. 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 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells. PNAS. 2019;116(48):23891-23893.

20. McVey S, et al. Aurora B Tension Sensing Mechanisms in the Kinetochore Ensure Accurate Chromosome Segregation. Int J Mol Sci. 2021 Aug; 22(16): 8818.

21. Luserna di Rora A, et al. The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window? Journal of Hematology & Oncology. 2019;12:123.

22. Du R, et al. Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy. 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.