Bcl-2/Bcl-xL Inhibition Increases the Efficacy of Mek Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models
Menée sur 53 lignées cellulaires de cancer du poumon non à petites cellules et de cancer du pancréas, cette étude évalue l'intérêt d'ajouter le navitoclax, un antagoniste de Bcl-2/Bcl-xL, à un composé appelé G-963, un inhibiteur de MEK, seul ou en combinaison avec un composé appelé GDC-0941, un inhibiteur de PI3KCA
Although MEK inhibition is predicted to cause cell death by stabilization of the pro-apoptotic BH3-only protein, BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-xL (BCL2/BCL2L1) antagonist, and a novel mitogen-activated protein kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single-agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture. Addition of the phosphatidylinositol 3-kinase (PI3K, PIK3CA) inhibitor, GDC-0941, to this treatment combination increases cell killing compared to double or single-agent treatment. Taken together, these data suggest the efficacy of agents that target the MAPK and PI3K pathways can be improved by combination with a Bcl-2 family inhibitor.
http://mct.aacrjournals.org/content/early/2013/03/08/1535-7163.MCT-12-0949.abstract