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
N Tan, M Wong, MA Nannini, R Hong, LB Lee… - Molecular cancer …, 2013 - AACR
N Tan, M Wong, MA Nannini, R Hong, LB Lee, S Price, K Williams, PP Savy, P Yue…
Molecular cancer therapeutics, 2013•AACRAlthough mitogen-activated protein (MAP)–extracellular signal-regulated kinase (ERK)
kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic
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 MAP kinase …
kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic
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 MAP kinase …
Abstract
Although mitogen-activated protein (MAP)–extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic 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 MAP 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 with 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. Mol Cancer Ther; 12(6); 853–64. ©2013 AACR.
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