659 Use of an MCL-1 inhibitor to overcome melanoma’s resistance to current therapy

Abstract

Listen

Translate article

Despite the recent advancement in treatment for melanoma, options are still limited for patients without BRAF mutations or in relapse. Melanoma’s resistance is known to be promoted by MCL-1, an anti-apoptotic protein, and/or Melanoma Initiating Cells (MICs). Targeting these two components may be a new alternative for melanoma treatment. We examined the effects of SC-2001, a MCL-1 inhibitor, alone or in combination, in treating melanoma, including MICs. The drug was tested in common melanoma lines and in short-term cultures of patient samples, including cells derived from tumors of patients relapsed from BRAF-targeted therapy or immunotherapy. We included melanoma cells with a variety of mutation status, including cells with or without the common BRAF, NRAS or NF1 mutations. We used multiple in vitro and in vivo assays and the ground-breaking CRISPR/Cas9 genome-editing technique for this study. By itself, SC-2001 significantly killed the bulk of melanoma cells in vitro and in vivo (p<0.01). However, even at high doses, SC-2001 alone did not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a small molecule BCL-2/BCL-XL/BCL-W inhibitor) decreased ALDH+ cells, disrupted primary spheres, and inhibited the self-renewability of MICs (p<0.05). All of these measurements are characteristics of MICs. In addition, using a low-cell-number mouse xenograft model, we examined the effects of the combination on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduced tumor formation of the relapsed patient sample significantly compared to either drug alone (P<0.05). Mechanistic studies with the CRISPR/Cas9 technology demonstrated that the upregulation of the pro-apoptotic proteins NOXA and BIM was a crucial factor in the combination-induced cell death. This suggests that the combination of MCL-1 and BCL-2 inhibitors is a promising treatment option for patients without BRAF mutations and those relapsed from current treatment.