KRAS mutations are found in 35% of lung cancer tumors, making it one of the most prevalent oncogenic drivers. These mutations are associated with a poor prognosis across all cancer types, including non–small-cell lung cancer (NSCLC). The KRAS protein is a small GTPase that hydrolyzes guanosine triphosphate to guanosine diphosphate to initiate downstream signaling, including activation of the MAPK pathway resulting in tumor induction and growth. The KRAS G12C mutation is found in 14% of all lung cancer cases and is associated with cigarette smoking. Sotorasib, a KRAS G12C inhibitor, received breakthrough status for the treatment of patients with advanced NSCLC and recently was approved as second-line monotherapy for patients with KRAS G12C–positive NSCLC. In a clinical trial of 126 patients with advanced NSCLC, sotorasib demonstrated a 37.1% response rate, a progression-free survival of 6.8 months, and a median overall survival of 12.5 months. Despite this approval, 85% of cancers with KRAS mutations do not have specific targeted therapies. Because of its high prevalence, there is a need for further KRAS-directed therapeutic agents. In an issue of Current Opinion in Structural Biology, Lorenz and colleagues published a review of the various approaches to developing drugs that treat KRAS-harboring tumors and the agents targeting KRAS that are in development. Most approaches are evaluating the RAS-binding domain of RAF1; however, targeting the RAF1 cysteine-rich domain interaction is another possible approach.
In addition to sotorasib, adagrasib and ARS-1620 are other drugs targeting the KRAS G12C mutation. In patients with NSCLC, adagrasib demonstrated a 45% response rate and an 8.2-month median duration of response. Also in development are proteolysis targeting chimeras (PROTACS), drugs that degrade targeted proteins such as the KRAS G12C mutation through bifunctional molecules and an E3-ligase protein. Early-stage research is ongoing for agents with novel mechanisms of action with peptidic KRAS drugs, switch I/II pocket inhibitors, and KRAS dimerizers being studied. KRAS inhibitors eventually fail to work as the disease acquires resistance to these agents. The various mechanisms behind resistance are also being evaluated in early studies of genetic alterations and circulating tumor DNA. KRAS variations appear to be involved in disease progression, and multiple genetic alterations appear to be involved in therapeutic agent escape mechanisms. It is likely that PROTACS, pan-KRAS inhibitors, and drugs that selectively target KRAS G12D will be the next drugs to emerge for treatment of KRAS-harboring tumors.
Source
Herdeis L, Gerlach D, McConnell DB, Kessler D. Stopping the beating heart of cancer: KRAS reviewed. Curr Opin Struct Biol. 2021;71:136-147.
