Mutations in the gene KRAS are the most frequent drivers of tumour development across the spectrum of human cancers. Despite this prevalence, mutant KRAS protein has remained an intractable therapeutic target. Writing in Nature, Canon et al. describe a small molecule that binds one form of mutant KRAS with high specificity and sensitivity, inhibiting the protein. The authors use animal models to analyse how the inhibitor works, and show that it can shrink tumours in patients. This is among the first evidence of a clinical response to a specific KRAS inhibitor.
KRAS is an enzyme that controls a signalling pathway crucial for cell growth, differentiation and survival. The inactive protein is bound by a guanosine diphosphate (GDP) molecule — replacement of GDP by guanosine triphosphate (GTP) facilitates conformational changes in KRAS that allow the enzyme to bind and activate downstream effector molecules. Nearly all cancer-promoting KRAS mutations prevent GTP breakdown, leaving KRAS in a permanently active state. One such mutation involves substitution of a glycine amino-acid residue for a cysteine residue. The resulting mutant protein, KRASG12C, is found infrequently in various cancers. It is most prevalent in lung cancer, and is responsible for approximately 12% of non-small cell lung cancers.
