DNA damage response永利皇冠app
DNA Damage Response Inhibition is an 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永利皇冠app
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永利皇冠app
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永利皇冠app
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永利皇冠app
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 damage repair永利皇冠app
The PARP (Poly ADP-ribose polymerase) protein repairs single breaks in DNA, which if unrepaired can lead to double strand breaks.1 Some cancers, such as those cause by BRCA mutations (including breast, ovarian, prostate and pancreatic cancer).2 cannot repair double strand breaks and rely on PARP to repair single strand breaks.1 Blocking PARP can force single strand breaks, and as there is no reliable system left to repair them, they accumulate and the cancer cell dies.1
Blocking cell growth and replication永利皇冠app
Wee1 is a protein kinase that helps to regulate the cell cycle by pausing it after DNA damage occurs, allowing cells time to repair the damage.3 Wee1 is overexpressed in many breast,3, lung,4 and colon cancer cancers,3 suggesting that the tumour relies heavily on this mechanism to survive. By inhibiting Wee1, the cell cycle continues without pausing, and the DNA damage isn’t repaired which leads to tumour cell death.3
AstraZeneca is currently investigating a potent and selective Wee1 inhibitor across several Phase I and Phase II trials in solid tumours.
Preventing damage being detected永利皇冠app
Ataxia telangiectasia and rad3 related (ATR) and Ataxia telangiectasia mutated (ATM) kinases are proteins involved in detecting DNA Damage, stabilising the DNA and recruiting the appropriate protein to fix the damage when DNA replication stalls.5 Inhibition of ATR or ATM can prevent damage from being detected or repaired, as well as allowing it to be carried over into the next phase of the cell cycle.6 This leads to an accumulation of damage, and ultimately, cell death.6
AstraZeneca’s pipeline currently includes both ATM and ATR inhibitors in Phase 1 development.
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 Biology.
6. Weber A and Ryan A, ‘ATM And ATR As Therapeutic Targets In Cancer’ (2015) 149 Pharmacology & Therapeutics
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