The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma

• Published in: PloS one Vol. 6; no. 9; p. e25264
• Main Authors: Huynh, Chanh, Poliseno, Laura, Segura, Miguel F, Medicherla, Ratna, Haimovic, Adele, Menendez, Silvia, Shang, Shulian, Pavlick, Anna, Shao, Yongzhao, Darvishian, Farbod, Boylan, John F, Osman, Iman, Hernando, Eva
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.09.2011; Public Library of Science (PLoS)
• Subjects: Aberration; Agar; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Analysis; Animal models; Animals; Benzazepines - pharmacology; Benzazepines - therapeutic use; Biology; Biotechnology; Breast cancer; Cancer metastasis; Cancer treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Colonies; Dermatology; Environmental health; Gene expression; Health aspects; Humans; Immunohistochemistry; Inhibition; Inhibitors; Interdisciplinary aspects; Leukemia; Medical prognosis; Medicine; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Metastases; Metastasis; Mice; Mutation; Neuroblastoma; Notch protein; Pathology; Real-Time Polymerase Chain Reaction; Receptors, Notch - metabolism; Secretase; Signaling; Stem cells; Survival analysis; Transcription; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025264

Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma.