Research Papers:

Combining a GSI and BCL-2 inhibitor to overcome melanoma’s resistance to current treatments

Nabanita Mukherjee, Adam Almeida, Katie A. Partyka, Yan Lu, Josianna V. Schwan, Karoline Lambert, Madison Rogers, William A Robinson, Steven E Robinson, Allison J Applegate, Carol M Amato, Yuchun Luo, Mayumi Fujita, David A. Norris and Yiqun G. Shellman _

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Oncotarget. 2016; 7:84594-84607. https://doi.org/10.18632/oncotarget.13141

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Nabanita Mukherjee1, Adam Almeida1, Katie A. Partyka1, Yan Lu1, Josianna V. Schwan1, Karoline Lambert1, Madison Rogers1, William A Robinson2, Steven E Robinson2, Allison J Applegate2, Carol M Amato2, Yuchun Luo1, Mayumi Fujita1, David A. Norris1,3, Yiqun G. Shellman1

1University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA

2Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA

3Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO 80220, USA

Correspondence to:

Yiqun G. Shellman, email: [email protected]

Keywords: melanoma stem cells, melanoma initiating cells, GSI-I, ABT-737, BRAF-WT melanoma

Received: August 04, 2016     Accepted: October 27, 2016     Published: November 05, 2016


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.

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