PTEN regulates sensitivity of melanoma cells to RO4929097, the γ-secretase inhibitor Journal Article


Authors: Nair, J. S.; Sheikh, T.; Ho, A. L.; Schwartz, G. K.
Article 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.
Keywords: protein kinase b; protein expression; human cell; drug efficacy; temozolomide; gene overexpression; melanoma; enzyme inhibition; combination chemotherapy; in vivo study; in vitro study; wild type; enzyme phosphorylation; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; melanoma cell; senescence; pten; drug sensitivity; breast cell; concentration response; gamma secretase; n (6,7 dihydro 6 oxo 5h dibenz[b,d]azepin 7 yl) 2,2 dimethyl n' (2,2,3,3,3 pentafluoropropyl)propanediamide; ro492907
Journal Title: Anticancer Research
Volume: 33
Issue: 4
ISSN: 0250-7005
Publisher: International Institute of Anticancer Research  
Date Published: 2013-04-01
Start Page: 1307
End Page: 1316
Language: English
PROVIDER: scopus
PUBMED: 23564767
DOI/URL:
Notes: --- - "Export Date: 3 June 2013" - "CODEN: ANTRD" - "Source: Scopus"