title: Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells.
abstract: 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.
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Mukherjee
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Almeida
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Karoline
authors.initials: K
authors.lastname: Lambert
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Robinson
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.|Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Norris
authors.affiliation: University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, USA.
authors.forename: Yiqun G
authors.initials: YG
authors.lastname: Shellman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics; D002470:Cell Survival; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C572884:SC-2001; D013449:Sulfonamides
keywords: SC-2001; cancer stem cells; drug-induced cell death; melanoma; melanoma stem cells