Mechanisms of resistance to direct KRAS G12C inhibition

KRAS mutations are the most common activating mutation in lung cancer and are identified in 25-30% of cases of lung adenocarcinoma. The clinical activity of molecularly targeted therapy in KRAS mutant lung cancer has been limited, as most prior approaches focused on downstream targets of the MAPK pathway, an approach which was largely ineffective. KRAS G12C is the most common subtype of activating KRAS mutation in NSCLC. Identification of a binding pocket of KRAS G12C enabled the development of covalent inhibitors (Ostrem et al. Nature, 2013), which selectively bind to the mutant cysteine and spare wild type or other mutant KRAS proteins (hereafter referred to as G12Ci). These drugs bind only to GDP-bound (i.e. inactive) KRAS G12C and trap the oncoprotein in its inactive state by preventing nucleotide exchange (Lito et al. Science, 2016). Of this new class of agents, two drugs (MRTX849 and AMG510) have demonstrated efficacy in early phase clinical trials, representing a remarkable breakthrough in the management of KRAS G12C mutant lung cancer. Acknowledging the limited number of patients treated thus far, response rates of 40-50% have been reported, demonstrating clinical activity far superior to prior molecularly targeted approaches for the management of KRAS mutant lung cancer. Despite this major advance it is clear that resistance to therapy, both primary and acquired, will remain a challenge and may in part be due to upstream receptor tyrosine kinase (RTK) signaling. Understanding the mechanisms of resistance to this new class of therapy is of paramount importance to improve the efficacy and durability of response, and for identifying rational combinatorial therapies for future clinical trials.