Abstract
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 (γ-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.
Highlights
Metastatic melanoma is one of the most devastating forms of skin cancer
Annexin V assays demonstrated that the combination dramatically increased apoptosis compared to DMSO or single drug treatment conditions for all seven melanoma cell lines tested (p < 0.05 or less) irrespective of the mutation status, but not for the melanocytes (Figure 1C)
The combination treatment resulted in the highest level of PARP cleavage relative to other treatments. This was again consistent for all the melanoma cell lines tested irrespective of the mutation status of BRAF or NRAS (Figure 1D)
Summary
Metastatic melanoma is one of the most devastating forms of skin cancer. It is the fifth most common cancer in men and the seventh in women with an estimated 76,380 new cases and 10,130 deaths for 2016 in the U.S [1]. BRAF-targeting drugs have provided a major breakthrough in melanoma treatment, but have limitations due to high relapse and increased resistance to therapy [3,4,5,6]. BRAF wild type (WT) tumors do not respond to molecular-targeted treatments and immunotherapy is the main treatment option for these patients [6]. In spite of the ground breaking progresses in melanoma treatment, relapse and lack of treatment options for BRAF-WT patients remains a crucial issue
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