Open AccessTargeting KRAS mutant lung cancer: light at the end of the tunnel
Author(s) -
Drosten Matthias,
Barbacid Mariano
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13168
Subject(s) - kras , mapk/erk pathway , cancer research , lung cancer , effector , targeted therapy , kinase , cancer , medicine , biology , bioinformatics , colorectal cancer , microbiology and biotechnology , oncology
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.