New way of targeting cancer’s most commonly mutated gene

Blocking a gene involved with cellular division and replication could provide clues in understanding how to target the most common mutation found in cancer, a new study shows.

Scientists at The Institute of Cancer Research, London, screened colorectal tumour cells with mutations to a gene called KRAS, which is mutated in 20% of human cancer, to identify genes these cells depend on to survive.

They found that cancer cells carrying KRAS mutations were genetically ‘addicted’ to the gene CDK1, a key player in cell cycle regulation.

Inhibiting CDK1 caused ‘synthetic lethality’, where cancer cells are left vulnerable by a genetic mutation and can be killed by blocking a second gene they have become reliant on for their survival.

In mice with KRAS-mutated tumours, chemically blocking CDK1 killed cancer cells and led to a 60% reduction in tumour weight, compared with mice treated with a placebo.

The study was published in the journal PLOS One and was funded by Cancer Research UK.

The KRAS gene regulates a complex signalling network in our cells which is thought to promote several characteristics of tumour growth.

'Vulnerable'

Mutated forms of KRAS are found in nearly a fifth of human cancers, but currently there are no therapies that successfully target the gene.

Scientists at the ICR used genetic screens of colorectal and pancreatic cancer cells with KRAS mutations to identify genes that cancer becomes addicted to for survival.

Genetically silencing CDK1 inhibited tumour cell growth in models of colorectal and pancreatic cancer with KRAS mutations, when compared to cells with normal KRAS genes.

Dr Chris Lord, Leader of the Gene Function team at the ICR, said: “Cancer cells are normally seen to gain advantage through genetic mutations, such as faster growth or the ability to spread. But mutations can also leave cancer cells vulnerable and over-reliant on other genes for their survival.

“Our research suggests that tumour cells with KRAS mutations are addicted to the gene CDK1 and can be killed when this gene is blocked. Mutations to the gene KRAS are found in a fifth of human cancer but at the moment there are no therapies directed against them. Our work provides more insight into how therapies could be designed that exploit this particular addiction.”