Cancerous tumours treated with cisplatin quickly become resistant to the drug, and researchers from MIT may have discovered why – a gene called PIDD.
Cisplatin is used in cancer treatment
PIDD, or p53-induced protein with a death domain, is switched on by p53 – a tumour suppressor gene. When levels of PIDD – which is thought to be involved in programmed cell death – are artificially increased in human lung cancer cells, they become more resistant to cisplatin.
“It is likely that PIDD is just one of many genes, in many pathways, involved in the drug resistance process,” said Trudy Oliver, “It’s not a simple phenomenon.” Oliver is a postdoctoral researcher at MIT and lead author of the paper.
Oliver and her colleagues originally set out to study cisplatin resistance in mice with a mutation in the gene Kras – which leads to the development of lung cancer and is present in around 30% of human lung cancer patients. Some of the mice also had defective versions of p53, which is mutated in around half of human lung cancers.
The researchers showed that cisplatin was effective against lung cancer in all mice, but was more potent in those with a functional p53 gene, shrinking the tumours. In comparison, tumours in mice with the defective gene were slowed.
After four doses of cisplatin, mice with a normal p53 developed resistant to the platinum-based drug and tumours started growing faster. The researchers analysed which genes were transcribed more as resistance developed, and identified several that are involved in DNA repair pathways – including PIDD.
Cisplatin is a doctor’s first line of defence against many cancers, including those of the lung, ovary and testes. It destroys tumour cells by binding to DNA strands and interrupting cell replication. This activates the cell’s DNA repair mechanism – which eventually can help the cells evade death. If the damage is too extensive to be repaired, the cell will undergo a programmed death.