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

Area of Science:

• Oncology
• Cancer Therapy
• Melanoma Research

Background:

• Current melanoma treatments face limitations in managing relapsed cases and lack options for BRAF wild-type patients unresponsive to immunotherapy.
• Melanoma Initiating Cells (MICs) are a resistant subpopulation implicated in treatment relapse, necessitating strategies to eliminate them.

Purpose of the Study:

• To investigate the efficacy of combining a gamma-secretase inhibitor (GSI) with ABT-737 in eradicating both bulk melanoma (non-MICs) and Melanoma Initiating Cells (MICs).
• To evaluate this combination therapy in diverse patient samples, including those relapsed from current treatments and with various genetic mutations (BRAF, NRAS, NF1).

Main Methods:

• Utilized multiple melanoma cell lines and patient-derived samples, including relapsed cases with diverse genetic backgrounds.
• Assessed treatment effects on cell viability, apoptosis, sphere formation, ALDH+ cell populations, and self-renewal capacity of MICs.
• Employed a low-cell-number mouse xenograft model to evaluate the *in vivo* tumor-initiating potential of MIC-enriched cultures.

Main Results:

• The GSI and ABT-737 combination significantly reduced non-MIC viability and induced apoptosis.
• The combination disrupted MIC sphere formation, decreased ALDH+ cells, and inhibited MIC self-renewability.
• In vivo studies demonstrated a significant reduction in tumor initiation from MIC-enriched cultures treated with the combination therapy.
• Mechanistic studies revealed that NOXA is essential for the observed cell death.

Conclusions:

• The combination of GSI and ABT-737 shows promise as a therapeutic strategy to overcome melanoma treatment relapse.
• This approach may offer a viable option for BRAF wild-type melanoma patients who do not respond to immunotherapy.
• The NOXA-dependent cell death pathway is critical for the efficacy of this combination treatment.