KRAS mutations have long been considered among the most challenging alterations to target in oncology. KRAS is one of the most commonly mutated oncogenes in human cancers, particularly in pancreatic, colorectal, and lung cancers.
For many years, KRAS was labeled 'undruggable' because the protein lacked a clear binding pocket for conventional small-molecule inhibitors. This perception changed with the development of covalent inhibitors that target the mutant KRAS G12C variant.
Sotorasib and adagrasib are KRAS G12C inhibitors approved for KRAS G12C-mutant non-small cell lung cancer. Research is ongoing to develop inhibitors for other KRAS variants, including G12D, G12V, and pan-KRAS inhibitors.