Targeting KRAS mutant lung cancer: light at the end of the tunnel

For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRAS(G12C) inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.

Automated summary

This article discusses the challenges of personalized medicine in treating KRAS mutant lung adenocarcinomas and highlights the recent breakthrough in developing selective KRAS(G12C) inhibitors. The mechanisms of resistance to these inhibitors and alternative therapeutic strategies to target KRAS oncogenic signaling are also explored. The article also examines the failure of MEK and ERK inhibitors in clinical trials and the potential of targeting RAF1 as a MAPK-independent activity. These developments are likely to provide new avenues for effectively treating KRAS mutant lung adenocarcinomas.