Abstract
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.
Highlights
The incidence of melanoma has been constantly increasing during the last decades [1]
In order to evaluate the potential use of RO4929097 in the adjuvant setting, the drug was initially tested on a panel of primary melanoma cell lines
The aggressiveness of melanoma, which is surprisingly high considering that it is among a handful of cancers whose dimensions are reported in millimeters, is due to the high degree of heterogeneity and plasticity combined with the chemoresistance of melanoma cells [38,39,40]
Summary
The incidence of melanoma has been constantly increasing during the last decades [1]. Adjuvant therapy after complete resection is recommended for thick primary melanoma with lymph node metastases, because recurrence rates are relatively high and overall survival is poor [2]. It is especially concerning that the conventionally used drugs for metastatic melanoma include dacarbazine and IL-2, both of which cause poor (,15% of cases) and transient responses [4]. Binding of DELTA (DLL 1/3/4) or JAGGED (JAG 1/2) ligands makes the receptors susceptible to metalloprotease- and gamma secretase-mediated proteolytic cleavage. This cleavage results in the release of NOTCH intracellular domain (NIC) from the plasma membrane and its translocation into the nucleus. NIC mediates the transcription of target genes, including basic helix-loop-helix transcription factors of the hairy and enhancer of split (HES) family and the HES-related repressor protein (HERP/HRT/HEY) family
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