title: OSU-03012 interacts with lapatinib to kill brain cancer cells.
abstract: We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills brain cancer cells. OSU toxicity was enhanced by the HSP90 inhibitor 17-N-Allylamino-17-demethoxygeldanamycin (17AAG) that correlated with reduced expression of ERBB1 and ERBB2. Inhibition of the extrinsic apoptosis pathway blocked the interaction between 17AAG and OSU. OSU toxicity was enhanced by the inhibitor of ERBB1/2/4, lapatinib. Knock down of ERBB1/2/4 in a cell line specific fashion promoted OSU toxicity. Combined exposure of cells to lapatinib and OSU resulted in reduced AKT and ERK1/2 activity; expression of activated forms of AKT and to a lesser extent MEK1 protected cells from the lethal effects of the drug combination. Knock down of PTEN suppressed, and expression of PTEN enhanced, the lethal interaction between OSU and lapatinib. Downstream of PTEN, inhibition of mTOR recapitulated the effects of lapatinib. Knock down of CD95, NOXA, PUMA, BIK or AIF, suppressed lapatinib and OSU toxicity. Knock down of MCL-1 enhanced, and overexpression of MCL-1 suppressed, drug combination lethality. Lapatinib and OSU interacted in vivo to suppress the growth of established tumors. Collectively our data argue that the inhibition of ERBB receptor function represents a useful way to enhance OSU lethality in brain tumor cells.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.forename: Thomas
authors.initials: T
authors.lastname: Ridder
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D016227:Benzoquinones / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D066246:ErbB Receptors / Q000235:genetics; D018773:Genes, erbB-1; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D000077341:Lapatinib; D008055:Lipids; D048369:MAP Kinase Kinase 1; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051059:PTEN Phosphohydrolase / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D016227:Benzoquinones; D000068579:Celecoxib; D000091342:Endoplasmic Reticulum Chaperone BiP; D066246:ErbB Receptors; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D000077341:Lapatinib; D008055:Lipids; D048369:MAP Kinase Kinase 1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D013449:Sulfonamides; C502778:ATG5 protein, human; C491997:BECN1 protein, human; C086724:Lipofectamine; C500894:OSU 03012; C112765:tanespimycin; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human; C482125:MAP2K1 protein, human; C494929:PTEN protein, human