Scientists have discovered a new strategy to kill cancer cells with defects in genes responsible for DNA repair and cell division.
They found that by using drugs to block a molecule called WEE1 – which keeps cell division under control until DNA has been properly checked for errors – they could force cancer cells to make so many mistakes in their genetic code that they could no longer survive.
The researchers, at The Institute of Cancer Research, London, used genetic screening techniques to uncover what makes cancer cells vulnerable to a drug known as MK-1775 which targets WEE1.
The study, published in the journal Molecular Cancer Therapeutics, found that the WEE1 inhibitor was particularly effective at killing cancer cells with mistakes in Fanconi anaemia and homologous replication genes, which are involved in DNA replication and repair.
By using a technique called gene silencing, the researchers showed that defects in four genes identified by the initial screen – CHK1, MYT1, FANCM and BRIP1 – led to a two- to four-times increase in susceptibility to the WEE1 inhibitor MK-1775, compared with cells with these genes intact.
A more detailed investigation into the effects of WEE1 inhibition, in human and mouse cancer cells grown in the lab, revealed that cells with defects in Fanconi anaemia and homologous recombination DNA repair genes begin to divide too early, with errors in the copied DNA, resulting in catastrophic chromosome damage and cell death.
The study was largely funded by the Netherlands Organisation for Scientific Research, The NIHR Biomedical Research Centre at the ICR and The Royal Marsden, and Cancer Research UK.
For most cell types, WEE1 inhibitors do not cause a huge problem because healthy cells have alternative ways of delaying cell division so that damaged DNA can be repaired.
However, certain cancer cells which already have errors in DNA repair and cell division processes respond differently to WEE1 inhibitors. They cannot stall cell division in order to repair their DNA, and start to divide too early. Inhibiting WEE1 also makes DNA unstable, causing DNA strands to sever.
Dr Nick Turner, Team Leader in Molecular Oncology at the ICR and Honorary Consultant at the Royal Marsden NHS Foundation Trust, said: “Our research has identified a group of cancers with errors in their systems for DNA repair which are particularly vulnerable to drugs that target the WEE1 protein.
“We have identified a treatment strategy that takes advantage of the in-built weakness of cancers – which tend to have weaker controls on their cell division than healthy tissue.
“Blocking WEE1 in cancer cells with defects in their DNA repair sends them early into cell division, even where they have catastrophic genetic damage, and that seems to send them to their deaths.”