Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRAS(G12C) can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRAS(G12C) in vitro, induced CRBN/KRAS(G12C) dimerization, and degraded GFPKRAS(G12C) in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRAS(G12C) in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRAS(G12C) underlies the lack of activity. We discuss challenges for achieving targeted KRAS(G12C) degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRAS(G12C).