RAS is an oncogene —a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. The natural, unchanged form of the KRAS gene is called wild-type KRAS. Knowing whether a cancer has a wild-type or mutated KRAS gene may help plan treatment. Mutations in the KRAS gene are the major driver of pancreatic, colon, and other cancers. The resulting protein controls multiple signaling pathways involved in cell growth and survival. In cancer, the gene is mutated to be permanently “on,” driving cells to excessively multiply and form cancers. There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS.
Although mutations in all three RAS oncogenes can cause cancer. KRAS mutations are the most common and there are currently no effective treatments available for patients with KRAS-mutant cancers. The majority of patients with pancreatic adenocarcinoma carry a mutation in or have amplification of KRAS and several drugs are in development to target RAS.
There is also a group of genes “upstream” of KRAS, called ERBB and these genes appears to become upregulated (more active) when KRAS is inhibited or blocked. In other words, when KRAS goes down, ERBB goes up and drives KRAS and other related genes back up again resulting in resistance to anti-cancer drugs.
To try to overcome this source of drug resistance, researchers at University of California San Diego School of Medicine combined the KRAS inhibitor MRTX1133 with the FDA-approved pan-ERBB inhibitor Gilotrif (afatinib) to treat human pancreatic cells. The combination of drugs was found to be much more effective than treatment with the KRAS inhibitor alone. The researchers then tested the drugs in mice with pancreatic cancer and found that mice treated with both drugs survived significantly longer than those treated with either drug alone.
The authors now recommend the drug combination be tested in clinical trials for human cancer patients. MRTX1133 is being developed by Mirati and is in early phase clinical trials.
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