Research inhibits cancer's ability to resist treatments

Related tags Cancer Dna

A team of researchers have discovered how a key enzyme involved in
repairing DNA is put together and how it works, a development that
opens up new drug therapies for making cancer cells more vulnerable
to attack.

The discovery is all the more important as current treatments are fast becoming obsolete. The cancer's ability to repair itself and develop resistance to the drug therapy has become a major headache for the pharmaceutical industry.

While the design of cancer chemotherapy has become increasingly sophisticated, no cancer treatment is 100 per cent effective against cancer. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumours, even those from the same tissue of origin.

In the study, the team characterised, in three dimensions, the polynucleotide kinase (PNK), a key enzyme involved in a cell's ability to repair single-strand and double-strand breaks in DNA.

Normally, when a single- or double-strand break occurs, the damaged ends need to be cleaned up before they can be rejoined as an early step in the repair process. PNK is one of the key enzymes required to "polish" the strand break ends. Without it, cells are more sensitive to agents such as ionising radiation or certain drugs that kill cells by damaging their DNA.

DNA, or deoxyribonucleic acid, is a large molecule shaped like a double helix found primarily in the chromosomes of the cell nucleus and contains the genetic information of the cell. Once damaged, cells have developed biochemical responses to repair the damage; when they can't be repaired, cells die if the damage is too toxic. Or, if the damage is not lethal, mutations can occur that lead to cancer.

"This gives us a clearer picture of how the enzyme works and opens up the possibility that we can develop drugs that inhibit cancer's ability to repair itself and resist treatments,"​ says biochemistry professor Mark Glover, the lead author in the paper published in today's issue of Molecular Cell.

The research may give some clues as to why some lung cancer patients stop responding to the drugs Tarceva (erlotinib) and Iressa (gefitinib).

These drugs stop the growth of certain cancers by targeting a signaling molecule vital to the survival of those cancer cells. They are effective in about 10 per cent of patients with non-small cell lung cancer (NSCLC). In this type of cancer, which often occurs in patients with no history of smoking, malignant cells carry mutations in a gene that encodes the epidermal growth factor receptor (EGFR).

Although these targeted therapies are initially effective in this subset of patients, the drugs eventually stop working, and the tumours begin to grow again. This is known as acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all.

Related topics Preclinical Research Ingredients

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