KRAS is a gene that is commonly mutated in cancer, especially in pancreatic, lung and colorectal cancers. Despite its importance, scientists have for many years been unable to create a drug that can inhibit function of the KRAS protein. Recently, several drugs have been created that can inhibit the function of KRAS proteins that have a “G12C” mutation. There is hope that these G12C inhibitors will be useful for treating cancer in patients who have this mutation. In this review we discuss the problems that we may encounter with these drugs, especially the development of drug resistance to G12C inhibitors, and the approaches that we could use to overcome this.

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRAS^G12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.