Scientists have discovered a new combination of drugs that could act as a promising treatment for people with certain types of lung cancer.
Lung cancer is one of the most common cancers in the world. Every year, it’s thought that around 2.21 million people die due to lung cancer, according to the World Health Organisation (WHO).1 Whilst some patients can be effectively treated with immunotherapy, this type of treatment doesn’t work for most patients.
More so, with only a quarter of people surviving more than five years after initial diagnosis, there is an urgent need to find new and effective treatments.
Now, a new study has shown that a combination of immunotherapy and a drug that blocks a common gene mutation in lung cancer could work as an effective treatment.
Researchers from the Francis Crick Institute conducted a study assessing the effects of combining immune checkpoint blockade with KRAS inhibitors in mice. They found that in tumours where there were already high numbers of active immune cells – something they labelled as ‘immune hot’ tumours – the treatment successfully controlled the cancer. However, in cases where the immune system was not able to mount a strong response, the combination treatment was ineffective.
In 2021, the first KRAS-inhibitor was approved for use in non-small-cell lung cancer cases with the KRAS G12C mutation.
The KRAS gene is part of the RAS family of genes which are found in about 20% of all cancer, including melanoma, bowel cancer and pancreatic cancer.
Whilst there are ongoing trials assessing its effectiveness alongside immunotherapy, most trials only involve patients who have already been through immune checkpoint blockade and have not responded. As immunotherapy has been unsuccessful, this suggests their tumours are not ‘immune hot’ and so, according to this study, they are also unlikely to respond to the combination of treatments.
The team at Francis Crick are now calling for clinical trials to include patients with ‘immune hot’ tumours, to ensure that the potentially effective combination is tested on those most likely to respond.
The researchers also investigated how KRAS mutations impact the tumours, the environment around it, and also the immune system. In lung cancer, they found that a mutated KRAS gene weakens signals which help activate the immune system while boosting hormone-like molecules which help create an environment that supports the tumour.
The team inhibited the mutated gene in mouse models and found that these pro-tumour effects did not occur. They found that within the tumour environment, there were fewer cells that suppress the immune system and more cytotoxic T cells which kill cancerous cells.
“In recent years, there has been a lot of attention on whether combining immune checkpoint blockade, a type of immunotherapy, with a KRAS-inhibitor could 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 one third of lung cancer cases, it is a promising therapeutic target,” explains Julian Downward, author and principal group leader and associate research director at the Crick.
“KRAS inhibitors are very new so there’s still a lot to learn about when they are most effective and which other treatments they can safely be combined with to give patients the best chance of living longer.
“Our study is an important part of this, suggesting that combining immune checkpoint blockade with a KRAS-inhibitor is likely to work in specific cancers. It is crucial this is factored into the design of future clinical trials,” explains Miriam Molina Arcas, author and principal research scientist in the Oncogene Biology laboratory at the Crick.