Scientific Basis for Advancement of Potent KRAS Inhibitors
The human body is a complex system with cells that are constantly signaling, sending each other millions of messages every second—including critical messages on how to best grow and spread. The genes responsible for ensuring these messages are accurate include the RAS family: KRAS, NRAS, and HRAS. Together, as part of the MAPK/ERK signaling pathway, the RAS family is responsible for controlling cell growth.
Known as oncogenes, when a gene in the RAS family becomes mutated, cells can grow and spread out of control, leading to cancer. The KRAS mutation was one of the first oncogenes discovered more than 30 years ago and is the most commonly mutated oncogene. Cancers stemming from RAS mutations account for nearly a quarter of all human cancers and contribute to 1 million deaths per year worldwide. Among the RAS family of oncogenes, KRAS gene mutations are the most common, making up to 85% of all RAS mutations.
Targeting mutations in oncogenes, like KRAS, has been valuable for researchers and drug developers. These types of mutations are not inherited—that is, they are created by mistakes during normal cell division—and drive the uncontrolled cell division and growth that eventually becomes cancer. Accordingly, these mutations are known as driver mutations because by themselves they cause cancer (Source: NIH).
Targeted treatment options have been developed and approved for several of the main driver mutations, with the exception of KRAS. Yet because KRAS mutations rarely co-occur with these other, more treatable oncogenic mutations, there are hundreds of thousands of KRAS G12C mutation positive patients are currently without a targeted treatment option. Mirati has developed adagrasib (MRTX849), as a potential treatment option for those patients.