Targeting Hypoxia Tolerance for Improved Therapy
April 18, 2013

A lack of oxygen, known as hypoxia, is a common condition for cancer cells in solid tumours. Hypoxia in tumours is a major limiting factor in successful cancer treatment; hypoxic cells require nearly three times as much radiation to kill. OCI Senior Scientist Dr. Bradly Wouters and collaborators studied the mechanisms that confer hypoxia resistance to cancer cells and recently identified one signalling pathway that, when inhibited, could improve the response to treatment.

The hypoxia inducible factor pathway (HIF) and protein kinase r-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 α (eIF2α) both play a role in helping cancer cells survive the hypoxic environment of a tumour. Inhibiting either pathway decreased the fraction of surviving cells in hypoxic zones to a similar extent. HIF inhibition did not result in an improved response to radiation therapy, whereas blocking the PERK/eIF2α pathway led to “a striking improvement in tumour response to treatment,” according to Dr. Wouters. The study demonstrated that the PERK/eIF2α pathway mediates resistance to repeated cycles of hypoxia and oxygenation in tumours and that these cells were particularly important for the recovery and growth of tumours following radiation therapy.

This work was supported by the Dutch Science Organization, the Dutch Cancer Society, the Ontario Ministry of Health and Long-Term Care, The Terry Fox Research Institute, The Ontario Institute for Cancer Research, The Canadian Institutes of Health Research, The European Union Seventh Framework Programme/METOXIA and The Princess Margaret Cancer Foundation.

PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Rouschop KM, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel AJ, Koritzinsky M, Wouters BG. Proceedings of the National Academy of Sciences.2013 March 19.
Reprinted from NRx - March 2013.
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