Scientists have shown how stomach cancers can develop resistance to a new class of drugs called ATR inhibitors by switching off the activity of two key genes – raising the possibility of outsmarting cancer by predicting drug resistance in advance.
The findings could pave the way for a genetic test to predict which patients are most likely to respond to ATR inhibitors and overcoming resistance through new combination treatments.
The study was led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and is published in the journal Cancer Research. It was funded by Cancer Research UK.
CRISPR used to identify genes involved
The scientists used the gene editing technology CRISPR in the lab to break or switch off each of 25,000 genes in cancer cells treated with ATR inhibitors, to identify which genes contributed to drug resistance.
Switching off either of two genes called SMG8 or SMG9 made cancer cells resistant to ATR inhibitors and led to increased activity of another gene called SMG1, which further drove drug resistance. But the researchers showed that when SMG8 and SMG9 were switched off, cancer cells remained able to repair their DNA even in the presence of ATR inhibitors.
They also found that ATR inhibitors lost their ability to rein in cell division in cancer cells which had SMG8 or SMG9 mutations.
The researchers now want to determine whether the results hold promise for patients treated in the clinic – with those whose cancers have genetic defects in SMG8, SMG9 or SMG1 responding differently to ATR inhibitors.
They hope to use this information to create a test which could select patients whose cancers are most likely to respond to ATR inhibitors, or else anticipate drug resistance in advance. It could also be possible to overcome drug resistance by creating drugs that disable the resistance mechanism.
Hope for new tests and treatments
Around 6,500 people are diagnosed with stomach cancer every year in the UK. One in four patients with advanced stomach cancer have tumours with genetic alterations in DNA repair genes which could make them susceptible to drugs like ATR inhibitors.
Study leader Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, said: “Our research has unpicked the genetic changes which are allowing some stomach cancers to dodge the effects of an exciting new class of treatment called ATR inhibitors.
“We believe our findings could lead to new tests and ultimately treatment strategies, to allow us to stay one step ahead of cancer. It could lay the groundwork for future clinical trials to test out new drug combinations and other treatment approaches designed to overcome cancer’s drug resistance.”
