After the first approval of the KRAS mutation treatment last year, the research fever has heated up.
One of the deadliest cancerous mutations of the KRAS gene was discovered in 1982. For more than 40 years, no treatment has been developed that can control the mutation of this gene, so this gene mutation cancer has been judged “unable to fight. the illness”.
The scientific journal Nature reported on the 25th that the development of a related treatment is accelerating after the US Food and Drug Administration (FDA) approved Sotorasib (trade name: Lumakras), a KRAS-targeted cancer treatment manufactured by Amgen, a US biotechnology company, reported last year (local time).
Cancer is a mutation in a protein involved in cell signal transduction, which causes cells to deviate from normal growth and differentiate too quickly. There are several proteins involved in cell signaling. Among them, the protein located in the center of the cell path web is clas. This is because it is involved in cell signaling pathways that regulate cell proliferation, maturation and death.
The kras protein exists in two states. When it binds to the GTP signaling molecule, it goes from the “off” state to the “on” state. When cancer-related mutations occur, they mostly stay “on” and are found in nearly all types of cancer. More than 80% of pancreatic cancers have a classic mutation, as do approximately 30% of lung adenocarcinomas and colorectal cancers. About a quarter of all cancers are defined as being due to classic mutations.
Sotorashib only targeted a specific mutation called G12C among several mutations in the clas gene. This mutation causes cancer by replacing glycine (G), the 12th amino acid in KRAS, with cysteine (C). Sotorashib blocks it, but the effect is temporary. Most people who respond early relapse after a few months.
On September 12, Amgen announced that in a recent clinical trial of Sotorasib, “progression-free survival (PFS),” which measures the time elapsed from a cancer-free state, was extended by one month compared to chemotherapy PFS. standard .. done. Only 28% of sotorashib-treated participants had a response. This is double that of those who responded to standard chemotherapy. However, it is said that over 70% of people with KRAS-positive lung cancer are not receiving help from new drugs.
Another problem is that this drug only produces short-term reactions and is erratic. Clinical studies have been conducted so far in patients with KRAS-induced advanced cancer who have not responded to other therapies, resulting in tumor growth arrest for more than six months. However, this was the case in less than a third of G12C lung cancer patients and less than a tenth of G12C colorectal cancer patients. After treatment, many tumors showed resistance to the drug.
Despite this limited success, Sotorasib’s approval revitalized the scene. In addition to Sotorashib, six types of treatments for the clath mutation are under development in the United States, including the adagrasib from Mirati Therapeutics, which is about to be approved by the FDA later this year. Channing Dare, a cancer biologist at the University of North Carolina in the United States, said, “I’ve never seen this level of excitement and confusion in the history of Kras-targeted drug research.”
“The decision to target G12C played a vital role in Sotorasib’s success,” said Kevan Shawcat, a professor of biochemistry at the University of California, San Francisco (UCSF), who laid the groundwork for the Sotorasib study. in 2013. Because cysteine (C) reacts chemically better than many other amino acids, it is easier to design drugs that bind to it. Adagrasib is also a G12C targeted treatment.
Most KRAS mutations have another mutation in the same location called G12D. It is a mutation in which D-aspartic acid replaces glycine and two types of treatments are being developed to target this. The clas protein is one of the three types of Ras (RAS) proteins Revolution Medicines, co-founded by Professor Shawcat, allows the other two types of Ras proteins, NRAS and HRAS, to take on the role of the clas protein or block mutations in all three proteins A “pan-RAS treatment” is developing.
The document is available at the following link (https://www.pnas.org/doi/10.1073/pnas.2123432119).
