The protein KRAS has for decades been considered a holy grail of cancer drug discovery. For most of that time, it has also been considered undruggable.
Among cancer-driving genes, few are as prominent as KRAS. First identified in 1982, KRAS mutations are now known to be involved in about 14% of human cancers. The KRAS protein is a small membrane-bound GTPase important for multiple cancer cell-signaling functions. It exists in two states. When bound to GDP, it is “off.” When GDP is exchanged for GTP (usually in response to various growth stimuli), KRAS is activated, or turned “on,” activating downstream signaling to promote cell proliferation and survival. KRAS returns to the “off” state when GTP is hydrolyzed to GDP. Cancers can arise when KRAS signaling gets stuck in the “on” state. Activation occurs through multiple mechanisms, most often through activating mutations of KRAS. Mutations activate KRAS by shifting the balance towards a GTP-loaded or “on” state, triggering tumor proliferation and survival. The central role of KRAS as a molecular switch driving cancer has made it the focus of drug discovery for decades.
KRASG12C is a specific KRAS mutation representing 12-14% of all KRAS mutations.
This KRAS mutation is found most prevalently in patients with non-small cell lung cancer (NSCLC), colorectal carcinoma (CRC), and pancreatic ductal adenocarcinoma (PDAC). While it has been a target of interest for many years, advances are only recently being made.
Frontier’s lead program is focused on KRASG12C and is distinct in that it targets direct inhibition of both the activated GTP-bound and inactive GDP-bound forms of KRASG12C. Drugs that target this profile provide an opportunity for treating patients that are not responsive to or have become resistant to first generation clinical inhibitors that only target GDP-bound (i.e., inactive form of the protein) KRASG12C, and they offer the potential for increased activity in patients with cancer.
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