title: PTEN regulates sensitivity of melanoma cells to RO4929097, the γ-secretase inhibitor.
abstract: De-regulated expression of components of the Notch signaling pathway is observed in malignant melanoma. This pathway is activated by catalytic cleavage of the Notch receptor by γ-secretase. Phase-I trials with RO4929097, a potent gamma secretase inhibitor (GSI), and other agents of this class have demonstrated clinical activity in patients with melanoma. An understanding of the mechanisms for de novo sensitivity and resistance to this class of drugs would be critical for future drug development. We treated a panel of Phosphatase and Tensin Homolog (PTEN)-null, -mutant and -wild-type human melanoma cell lines with RO4929097 and evaluated the efficacy alone and in combination with chemotherapy. Although cleaved Notch-1 formation was observed in all the cell lines, RO4929097-induced senescence or apoptosis was achieved only in PTEN-wild-type cell lines in which gamma-secretase inhibition with an induction of PTEN expression and decreased AKT/PKB (protein kinase B) phosphorylation in addition to transcriptional suppression at the Hairy and enhancer of split-1 (HES1) gene promoter. Overexpression of wild-type PTEN in PTEN-null and -mutant cell lines, and studies with isogenic breast cell lines that differ only in PTEN status, confirmed the importance of PTEN expression for conferring tumor cell susceptibility to RO4929097. Furthermore, in PTEN-expressing rapidly accelerated fibrosarcoma 1 (B-RAF)-mutant melanoma cells, RO4929097 enhanced the effect of temozolomide both in vitro and in vivo. These results indicate that tumor cell susceptibility to a GSI, whether alone or in combination with chemotherapy, are reliant upon reducing AKT phosphorylation and hence GSI in combination with chemotherapy may be useful as a new therapeutic approach in treating PTEN-wild-type melanoma.
authors.affiliation: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. nairj@mskcc.org
authors.forename: Jayasree S
authors.initials: JS
authors.lastname: Nair
authors.forename: Tahir
authors.initials: T
authors.lastname: Sheikh
authors.forename: Alan L
authors.initials: AL
authors.lastname: Ho
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D051059:PTEN Phosphohydrolase; D034741:RNA, Small Interfering; C494929:PTEN protein, human; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons