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 KRASG12C 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.