Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models
Menée sur des lignées cellulaires et à l'aide d'un modèle murin de cancer du poumon, cette étude met en évidence l'intérêt de combiner un inhibiteur de la signalisation BCL-XL, le navitoclax, et un inhibiteur de MEK pour le traitement des cancers présentant des mutations du gène KRAS
KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers. º A MEK inhibitor-based synthetic lethal screen in KRAS mutant cancers identified BCL-XL º Combined inhibition of BCL-XL and MEK induces marked apoptosis in KRAS mutant cancers º Epithelial-to-mesenchymal transition predicts insensitivity to BCL-XL/MEK inhibition º Combined BCL-XL/MEK inhibition causes tumor regressions in KRAS mutant cancer models