title: 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.
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.
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tan
authors.forename: Maureen
authors.initials: M
authors.lastname: Wong
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Nannini
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hong
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.forename: Stephen
authors.initials: S
authors.lastname: Price
authors.forename: Karen
authors.initials: K
authors.lastname: Williams
authors.forename: Pierre Pascal
authors.initials: PP
authors.lastname: Savy
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D007191:Indazoles; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D051020:bcl-X Protein; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C494811:BCL2L1 protein, human; C528561:navitoclax