Direct Targeting Mutation in Non-Small Cell Lung Cancer: Focus on Resistance.
Fiche publication
Date publication
mars 2022
Journal
Cancers
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BEAU-FALLER Michèle, Dr GUERIN Eric, Dr PENCREACH Erwan, Dr VALLAT Laurent, Dr REITA Damien, Pr MASCAUX Céline
Tous les auteurs :
Reita D, Pabst L, Pencreach E, Guérin E, Dano L, Rimelen V, Voegeli AC, Vallat L, Mascaux C, Beau-Faller M
Lien Pubmed
Résumé
KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The mutations favor the active form with inhibition of GTPAse activity. mutations are often with poor response of EGFR targeted therapies. mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12-14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed G12C mutation.
Mots clés
KRAS G12C inhibitors, KRAS mutations, non-small cell lung cancer, phenotypic changes, resistance mechanisms
Référence
Cancers (Basel). 2022 Mar 4;14(5):