DNA damage response

Targeting the DNA repair process to block tumour cells' ability to reproduce


What is DNA damage response and why is it important?

DNA Damage Response Inhibition is an innovative new anti-cancer platform which could revolutionise the treatment of cancer. It works by exploiting DNA Damage Response defects which are specific to cancer cells, and kills them whilst sparing normal cells.1

AstraZeneca is pioneering this new treatment paradigm. We believe it is a crucial step forward in our aim of one day eliminating cancer as a cause of death.


The science behind DNA Damage Response Inhibition

Every day, DNA in our cells is damaged thousands of times by natural causes and external factors. If not corrected, this DNA damage could eventually lead to cancer.1 The body has developed systems to protect the cells from DNA damage, called the DNA Damage Response or DDR.1

A faulty DNA Damage Response system helps cancer develop, as it allows mutations that promote uncontrolled cell growth.2 Cancer cells with a DNA Damage Response deficiency are heavily reliant on remaining ‘back up’ DNA Damage Response systems.1

DNA Damage Response Inhibition exploits these defects by blocking the remaining response systems cancer cells are relying on to survive, which in turn causes them to die. Healthy cells are not vulnerable to this type of treatment.1


What we're working on

AstraZeneca is committed to investigating the potential of DNA Damage Response Inhibition across a range of tumour types. We currently have five compounds being investigated in clinical trials. The mechanism of action of DNA Damage Response Inhibitors suggests that they can be combined with other DNA Damage Response Inhibitors, immuno-oncology agents and targeted therapies.



Inhibiting stages in the DNA damage response pathway


References

1. O’Connor M, ‘Targeting The DNA Damage Response In Cancer’ (2015) 60 Molecular Cell
2. Jackson S and Bartek J, ‘The DNA-Damage Response In Human Biology And Disease’ (2009) 461 Nature
3. Vriend L and others, ‘WEE1 Inhibition And Genomic Instability In Cancer’ (2013) 1836 Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
4. De Witt Hamer P and others, ‘WEE1 Kinase Targeting Combined With DNA-Damaging Cancer Therapy Catalyzes Mitotic Catastrophe’ (2011) 17 Clinical Cancer Research
5. A. Maréchal and L.Zou, ‘DNA Damage Sensing by the ATM and ATR Kinases’ (2013) Cold Spring Harb Perspect Biol
6. Weber A and Ryan A, ‘ATM And ATR As Therapeutic Targets In Cancer’ (2015) 149 Pharmacology & Therapeutics



Veeva ID: Z4-4978
Date of next review: May 2018