Journal
ONCOTARGET
Volume 7, Issue 51, Pages 84594-84607Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13141
Keywords
melanoma stem cells; melanoma initiating cells; GSI-I; ABT-737; BRAF-WT melanoma
Categories
Funding
- VA [1048349, 5I01BX000141-07] Funding Source: Federal RePORTER
- NCI NIH HHS [P30 CA046934] Funding Source: Medline
- NIAMS NIH HHS [P30 AR057212] Funding Source: Medline
- BLRD VA [I01 BX000141] Funding Source: Medline
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Major limitations of current melanoma treatments are for instances of relapse and the lack of therapeutic options for BRAF wild-type patients who do not respond to immunotherapy. Many studies therefore focus on killing resistant subpopulations, such as Melanoma Initiating Cells (MICs) to prevent relapse. Here we examined whether combining a GSI (gamma-Secretase Inhibitor) with ABT-737 (a small molecule BCL-2/BCL-XL/BCL-W inhibitor) can kill both the non-MICs (bulk of melanoma) and MICs. To address the limitations of melanoma therapies, we included multiple tumor samples of patients relapsed from current treatments, with a diverse genetic background (with or without the common BRAF, NRAS or NF1 mutations) in these studies. Excitingly, the combination treatment reduced cell viability and induced apoptosis of the non-MICs; disrupted primary spheres, decreased the ALDH+ cells, and inhibited the self-renewability of the MICs in multiple melanoma cell lines and relapsed patient samples. Using a low-cell-number mouse xenograft model, we demonstrated that the combination significantly reduced the tumor initiating ability of MIC-enriched cultures from relapsed patient samples. Mechanistic studies also indicate that cell death is NOXA-dependent. In summary, this combination may be a promising strategy to address treatment relapse and for triple wild-type patients who do not respond to immunotherapy.
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