Work

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

Year: 2016

Type: article

Abstract: // Nabanita Mukherjee 1 , Adam Almeida 1 , Katie A. Partyka 1 , Yan Lu 1 , Josianna V. Schwan 1 , Karoline Lambert 1 , Madison Rogers 1 , William A Robinson 2 , Steven E Robinson 2 , Allison J Applegate 2 , Carol M Amato 2 , Yuchun Luo 1 , Mayumi Fujita 1 , David A. Norris 1, 3 , Yiqun G. Shellman 1 1 University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA 2 Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA 3 Department 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 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.13141