The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.
The KRAS gene provides your body with instructions for making a protein called K-Ras, which plays a central role in the signaling of a number of cellular pathways that regulate cell growth and proliferation. The K-Ras protein is a GTPase, which means it converts a molecule called guanosine triphosphate (GTP) into another molecule called guanosine diphosphate (GDP). Like a switch, the K-Ras protein is turned on and off by these GTP and GDP molecules. To transmit signals, the K-Ras protein must be turned on by binding to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.
While most mutations in genes are expected to cause their inactivation, with KRAS genes the opposite occurs - they become more active in signalling. With KRAS mutations, the GTPase is inactivated, meaning that GTP continues to engage the switch, and the Ras signalling function is unable to be turned "off".
KRAS mutations are found in many human cancers, with the highest prevalence in pancreatic adenocarcinomas (90%), colorectal cancers (45%) and lung cancers (35%). KRAS mutations are also predictive of a very poor response to colorectal cancer therapies, such as panitumumab and cetuximab. Targeted therapies that can block the function of mutant KRAS protein, but not the wild type KRAS, would be transformative in the successful treatment of a large number of cancer indications.
“KRAS mutations occur in a large number of cancers and represent a tremendous unmet clinical need, making for a highly desirable drug target. These mutations are detected in up to one‐fourth of all human cancers, particularly lung, colorectal, pancreatic, and thyroid. Selectively targeting the mutant forms of KRAS without inhibiting wild type KRAS function has been the focus of intense research for over two decades, with limited success. It is therefore very exciting that COTI‐219, which is designed to be selective against the mutant form of KRAS, is shown to be efficacious in multiple pre‐clinical tumor model systems." - Alison Silva, President of Critical Outcome Technologies Inc.