Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells
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Nabanita Mukherjee1, Yan Lu1, Adam Almeida1, Karoline Lambert1, Chung-Wai Shiau2, Jung-Chen Su2, Yuchun Luo1, Mayumi Fujita1, William A. Robinson3, Steven E. Robinson3, David A. Norris1,4 and Yiqun G. Shellman1
1University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA
2Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
3Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, USA
4Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO, USA
Yiqun G. Shellman, email: Yiqun.Shellman@ucdenver.edu
David A. Norris, email: David.Norris@ucdenver.edu
Keywords: melanoma stem cells, cancer stem cells, drug-induced cell death, melanoma, SC-2001
Received: December 22, 2015 Accepted: March 28, 2016 Published: April 12, 2016
MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma’s resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melanoma), and melanoma-initiating-cells (MICs). By itself, SC-2001 significantly kills melanoma cells under monolayer conditions in vitro and in a conventional mouse xenograft model. However, even at high doses (10μM), SC-2001 does not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a BCL-2/BCL-XL/BCL-W inhibitor) significantly decreases ALDH+ cells, disrupts primary spheres, and inhibits the self-renewability of MICs. These results were observed in multiple melanomas, including short term cultures of relapsed tumors from current treatments, independent of the mutation status of BRAF or NRAS. Using a low-cell-number mouse xenograft model, we examined the effects of these treatments on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduces tumor formation significantly compared to either drug alone. Mechanistic studies using shRNA and the CRISPR-Cas9 technology demonstrated that the upregulation of pro-apoptotic proteins NOXA and BIM contribute to the combination-induced cell death. These results indicate that the MCL-1 inhibitor SC-2001 combined with ABT-737 is a promising treatment strategy for targeting melanoma.
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