Scientists from Francis Crick Institute, in the UK, found that using immunotherapy with a drug that blocks a common genetic mutation in lung cancer could be a promising new combination therapy for certain types of lung tumours. His work, published in the magazine “Scientists progress”could help select patients for clinical trials to confirm whether this combination therapy is effective in humans.
Around 1.8 million people die each year from lung cancer, making it the leading cause of cancer death worldwide. Although some people receive effective treatment with immunotherapy, it does not work for most patients. .
Given that only a quarter of people survive more than five years after the diagnosis, there is an urgent need to find new treatments or new combinations of existing drugs.
“Much attention has been paid in recent years to the question of whether combining immune checkpoint blockade, a type of immunotherapy, with a KRAS inhibitor might be effective. This inhibitor works by blocking a mutated version of KRAS.a gene that helps control cell growth and death. As the mutation is present in about a third of lung cancer cases, it is a promising therapeutic target,” explains Julien downauthor and senior group leader and associate research director at Crick.
In their study, the researchers investigated whats effects of combining blocking checkpoints immune systems with KRAS inhibitors in mice. In tumors in which there were already high numbers of active immune cells, called “hot immune” tumors, the treatment was successful in controlling the cancer. However, in cases where the immune system was unable to produce a strong response, the combination treatment was ineffective.
In 2021, the first KRAS inhibitor was approved for use in non-small cell lung cancer with the KRASG12C mutation. And there are several ongoing clinical trials exploring the effectiveness of combining this inhibitor with immune checkpoint blockade.
However, most of these trials only include patients who have previously experienced immune checkpoint blockade and have failed to respond. Given that immunotherapy failed, this suggests that their tumors are not “hot immune” and therefore, according to this study, are not likely to respond to combination treatments either.
Researchers call for clinical trialss include patients with “immunocompromised” tumours, pto ensure that the potentially effective combination is tested in people most likely to respond.
“KRAS inhibitors are very new, so there is still a lot to learn about when they are most effective and what other treatments they can be safely combined with to give patients the best chance of living longer,” says he. Miriam Molina Arcas, author and principal investigator of the Oncogenic Biology Laboratory of Crick-. Our study is an important part of this, as it suggests that combining immune checkpoint blockade with a KRAS inhibitor may work in certain types of cancer. It is crucial that this be taken into account in the design of future clinical trials. »
The team also investigated impact of the KRAS mutation on the tumor, the environment and the immune system and found that in lung cancer, mutated KRAS weakens signals that help activate the immune system, while enhancing hormone-like molecules that help create an environment that supports the tumor .
When they inhibited the mutated gene in mouse models, these pro-tumor effects did not occur. For example, around the tumor there were fewer cells that suppress the immune system and more cytotoxic T cells that kill cancer cells.
The KRAS gene is a member of the RAS gene family that is implicated in approximately 20% of all cancers, including melanoma, bowel cancer, and pancreatic cancer.
Scientists will continue to study the role of this gene family in cancer, including investigating how the immune system can be stimulated to kill cancer cells that have developed resistance to RAS inhibitors.