Issues

Many mutations that activate KRAS by raising the abundance of GTP-bound (active) protein are recognized to be oncogenic. However, Zafra and colleagues found that the effects of individual KRAS-activating mutations depended strongly on the specific amino acid–residue change and where the mutant allele was expressed. For example, Kras^G12C or Kras^G12D expression in the pancreas caused rapid tumorigenesis, whereas Kras^G13D expression caused slower pancreatic tumorigenesis, and Kras^G12R expression caused almost no pancreatic tumorigenesis even after one year. Mutation type also affected drug sensitivity, with Kras^G13D-expressing pancreatic organoids exhibiting sensitivity to EGFR inhibition and Kras^G12C-expressing pancreatic organoids being sensitive to Kras^G12C-specific inhibitors only in the context of EGFR suppression. For more information, see the article by Zafra and colleagues on page 1654.