Working with a new class of cancer drugs called G12C KRAS inhibitors, researchers at the Francis Crick Institute and The Institute of Cancer Research (ICR), London, developed drug combinations to stay ahead of drug resistant tumors. They published their research in the journal Science Translational Medicine.
Cancer cells often develop resistance to drug treatments. Many are initially susceptible to chemotherapy, but over time develop resistance, causing researchers to work to develop new drugs that attack the cancer by way of different mechanisms or to find combination therapies that simultaneously kill the cells in different ways.
Mutations in the KRAS gene are found in 14% of lung adenocarcinomas, which is the most common type of lung cancer. It is a particularly deadly form with few if any effective treatments for most patients. About eight out of 10 patients die within five years of diagnosis. In the UK alone, about 2,800 people are diagnosed with lung cancers with the G12C KRAS mutation.
Lung adenocarcinoma is a type of non-small cell lung cancer. NSCLCs make up 80% of lung cancers, and of these about 50% are adenocarcinomas. It is the most common lung cancer in women, Asians and individuals under the age of 45. It is also, unexpectedly, more common in non-smokers than people who currently smoke. Contributing factors are genetics, secondhand smoke, and radon exposure.
“It’s likely that tumors will develop resistance to the new drugs, so we need to stay one step ahead,” said Julian Downward, senior author of the study who led the research. “We found a three-drug combination that significantly shrank lung tumors in mice and human cancer cells.”
Downward added, “Tumors treated with the combination shrank and stayed small, whereas those treated with the G12C KRAS inhibitor alone tended to shrink at first but then start growing again after a couple of weeks. Our results suggest that it would be worth trying this combination in human trials in the coming years, to prevent or at least delay drug resistance.”
The other two drugs in the cocktail block the mTOR and IGF1R pathways, which had previously been tested in cancer patients. There are mTOR inhibitors on the market, such as rapamycin and temsirolimus (Pfizer’s Torisel). Currently, IGF1R inhibitors are experimental drugs in the clinical trial stage.
The researchers utilize cancer cells from patients with the G12C KRAS mutation, which they then edited to block the activity of 16,019 different genes. They then treated the edited cells with drugs that KRAS mutational cancer typically respond to.
“We found that cell lines without the MTOR gene were significantly more vulnerable to both KRAS and IGF1R inhibitors,” said Miriam Molina-Arcas, senior laboratory research scientist at the Crick. “When we blocked all three pathways, the mutant cancer cells were simply unable to survive. This makes it a promising avenue for human trials in the coming years, although this is still early research. Promising results in mice and cells can tell us what’s worth trying, but it’s impossible to predict how patients will respond until we actually try.”
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