The study paves the way to overcoming drug resistance in stomach cancer

Scientists have shown how stomach cancer can escape the effects of a promising new experimental treatment – increasing the ability to outsmart cancer by predicting drug resistance in advance.

Their new study found that stomach cancer can develop resistance to a new class of drugs called ATR inhibitors by turning off the activity of two key genes.

The findings could pave the way for a genetic test to predict which patients are more likely to respond to ATR inhibitors and open the possibility of overcoming resistance with new combination therapies.

The research was carried out by a team from the Institute of Cancer Research in London and the Royal NHS Foundation Marsden and published in the journal Cancer research.

Identification of genes involved in drug resistance

The scientists used CRISPR gene-editing technology in the lab to break or turn off each of the 25,000 genes in cancer cells treated with ATR inhibitors to determine which genes contributed to drug resistance.

Turning off one of the two genes, called SMG8 or SMG9, made the cancer cells resistant to ATR inhibitors and also increased the activity of another gene called SMG1, further contributing to drug resistance.

ATR inhibitors work by blocking a protein called ATR, which normally helps cancer cells repair their DNA and plays an important role in cell division. When ATR is blocked, cancer cells accumulate DNA damage and eventually die.

But the researchers showed that when SMG8 and SMG9 were disabled, 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 inhibit cell division cancer cells who had SMG8 or SMG9 mutations.

Development of a genetic test

Researchers now want to determine whether the promising results for patients treated at the clinic — for those with cancer genetic defects in SMG8, SMG9, or SMG1 respond differently to ATR inhibitors.

They hope to use this information to develop a test that could select patients whose cancers are most likely to respond to ATR inhibitors, or predict drug resistance in advance. It would also be possible to overcome drug resistance by creating drugs that disable the resistance mechanism.

Researchers at the Institute of Cancer Research (ICR) and The Royal Marsden have been involved for several years in the clinical development of ATR inhibitors, including identifying genes that could select patients for treatment and targeting early-stage drugs to patients clinical trials.

Early drug trials were promising, but inevitably many patients developed drug resistance.

Around 6,500 people are diagnosed with stomach cancer every year in the UK. About one in four patients with advanced gastric cancer have tumors with genetic changes in DNA repair genes that can make them susceptible to drugs such as ATR inhibitors.

A new promising treatment option

Study leader Professor Chris Lord, Professor of Cancer Genomics at the Institute of Cancer Research in London, said: “Our research has identified genetic changes that allow some types of stomach cancer to escape the effects of an exciting new class of treatment called ATR inhibitors.

“ATR inhibitors represent a promising and much-needed new treatment option for people with gastric cancer, so it is important to understand how resistance can arise. We believe our findings may lead to new tests and, ultimately, treatment strategies that will allow us to stay that way. one step ahead of the river.

“Our discovery shows that three key genes are involved in making gastric cancer resistant to ATR inhibitor treatment. This could lay the foundation for future clinical trials to test new drug combinations and other treatment approaches aimed at overcoming drug resistance in cancer.”

Dr Irene Chong, senior author and consultant clinical oncologist and clinician at The Royal Marsden NHS Foundation Trust, said: “As a clinician treating gastric cancer, I am acutely aware that new strategies are urgently needed for patients with limited treatment options. Our study suggests that ATR inhibitors may represent an important therapeutic option for subgroups of patients with stomach cancer, and our work has revealed a new resistance mechanism that may help us understand how we can overcome drug resistance. This could eventually lead to new treatment strategies in the future. I would like to thank my PhD colleague Dr. Marta Llorca Cardenoza for his tireless work on this project, as well as our colleagues who worked together.”

Helps overcome drug resistance

Professor Christian Helin, chief executive of the Institute of Cancer Research in London, said: “ATR inhibitors are exciting treatments for many types of cancer, but like most cancer drugs they are associated with unwanted side effects, so it may not be possible to use the right dose. Another problem is that ATR inhibitors can also stop working if the cancer develops resistance to the drug.

“By identifying genetic changes that can make gastric cancer resistant to treatment, this study could pave the way for future tests that can select patients who will respond better to ATR inhibitors. I hope that these findings will lead to new treatment strategies for patients that can overcome or prevent drug resistance.”

Dr Sam Godfrey, Cancer Research UK’s head of information research, said: “Drug resistance is a common problem in cancer treatment, so predicting or even stopping it could allow us to use existing cancer treatments more effectively.

“It’s exciting to see a clear approach to overcoming resistance stomach cancer, for which several treatments are available. As new treatments undergo clinical trials, studies like this give us an important indication of which patients may benefit most from new drugs.”