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Published on: June 7, 2015
Targeting radiation-resistant hypoxic tumour cells through ATR inhibition
I M Pires1, M M Olcina, S Anbalagan
1Department of Oncology, The Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford OX3 7DQ, UK.
Background:
Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is therefore essential that strategies continue to be developed to target hypoxic cancer cells. Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy.
Methods:
Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE-821, in hypoxic conditions and its potential as a radiosensitiser.
Results:
VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Consistently, ATR inhibition sensitised tumour cell lines to a range of oxygen tensions. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition.
Conclusion:
These findings suggest that ATR inhibition represents a novel strategy to target tumour cells in conditions relevant to pathophysiology and enhance the efficacy of radiotherapy.
Insights
Inhibiting the DNA damage response kinase ATR with VE-821 sensitizes hypoxic tumor cells to radiotherapy. This approach enhances radiation-induced cell death and targets aggressive tumor fractions.
Area of Science:
- Oncology
- Cancer Biology
- Radiotherapy
Background:
- Solid tumors often contain hypoxic regions, making cancer cells resistant to radiotherapy.
- Hypoxic cells are the most aggressive tumor fraction, necessitating targeted treatment strategies.
- Inhibiting the DNA damage response (DDR) is a potential method to sensitize hypoxic tumor cells to radiotherapy.
Purpose of the Study:
- To investigate the cellular effects of ATR kinase inhibition using VE-821 under hypoxic conditions.
- To evaluate the potential of ATR inhibition as a radiosensitizer for hypoxic tumor cells.
Main Methods:
- Utilized a selective ATR inhibitor, VE-821, to study its effects on cancer cells in hypoxic environments.
- Assessed ATR-mediated signaling, DNA damage induction, and cell viability in response to VE-821 and radiation.
- Investigated the link between ATR inhibition and the hypoxic response regulator, HIF-1.
Main Results:
- VE-821 effectively inhibited ATR signaling and induced DNA damage in hypoxic conditions.
- ATR inhibition sensitized various tumor cell lines to radiation across different oxygen tensions.
- VE-821 significantly increased radiation-induced cell death in hypoxic tumor cells.
- Demonstrated a novel link between ATR inhibition and reduced HIF-1 stabilization and activity.
Conclusions:
- ATR inhibition is a promising strategy for targeting tumor cells in pathophysiologically relevant hypoxic conditions.
- Targeting ATR can enhance the efficacy of radiotherapy by sensitizing hypoxic tumor cells.
- This approach offers a novel therapeutic avenue for improving cancer treatment outcomes.
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