KRAS mutations are the most common gain-of-function alterations in lung adenocarcinoma
(LADC) in the western countries. Although the different mutations of the KRAS gene
have been identified decades ago, the development of drugs targeting the KRAS protein
directly have not been successful due to the lack of small molecule binding sites
and the extremely high affinity to cellular GTP. Indirect strategies to inhibit KRAS
(e.g. inhibitors of farnesyltransferase, prenylation, synthetic lethal partners and
KRAS downstream signaling) have so far also failed. In recent times, however several
compounds have been developed that target subtype- specific KRAS mutations. Covalent
KRAS G12C-specific inhibitors showed the most promising preclinical results. Below,
we summarize the predictive and prognostic value of KRAS mutations in LADC as well
as the current targeting strategies.
