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

Abstract

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.

BRAF V600E and previously unidentified KRAS G12C mutations in odontogenic tumors may affect MAPK activation differently depending on tumor type

“…1,5 Moreover, the KRAS G12C mutation could be a new therapeutic target for wild-type BRAF odontogenic tumors thanks to the recent development of KARS G12C inhibitors. 29 Other limitations of this study are due to the absence of KRAS G12C mutation-specific antibody to detect the protein expression in tissue samples and a difficulty in establishing MOT cell lines to clarify the detailed mechanisms of BRAF genotype-phenotype discordance.…”

“…However, reporting the previously unidentified mutation can broaden our understanding of oncogenes in odontogenic tumors and demonstrate an additional genetic difference other than BRAF V600E between AFO and odontoma, which may serve as an evidence to reclassify AFO as a separate entity in the WHO Classification of Head and Neck Tumors 1,5 . Moreover, the KRAS G12C mutation could be a new therapeutic target for wild‐type BRAF odontogenic tumors thanks to the recent development of KARS G12C inhibitors 29 . Other limitations of this study are due to the absence of KRAS G12C mutation‐specific antibody to detect the protein expression in tissue samples and a difficulty in establishing MOT cell lines to clarify the detailed mechanisms of BRAF genotype–phenotype discordance.…”

KRAS Inhibitors and Target Engagement Technology: From Undruggable to Druggable Targets in Cancer Therapeutics

“…The table below show a KRAS_G12C exchange assay and a KRAS_G12C pERK assay, where the symbols indicate IC 50 for † ≤ 100 nM, †† > 100 nM but ≤ 1 μM, ††† > 1 μM but ≤ 5 μM, and †††† > 5 μM but ≤ 10 μM. …”

Small-Molecule Inhibitor of the Oncogenic KRASG12C Mutant for the Treatment of Currently Incurable Cancer

“…The table below shows IC 50 values or inhibition behavior achieved by the racemate and two stereoisomers. Also, results of HTRF and Western blot assays are given. …”