MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Metastatic melanoma poses treatment challenges, especially for patients lacking genetic markers for targeted therapy or unresponsive to immunotherapy.
• Existing therapies like targeted agents and immune checkpoint inhibitors have limitations, necessitating novel therapeutic strategies.
• The apoptotic/anti-apoptotic system, a successful target in leukemia, presents an appealing avenue for melanoma treatment.

Purpose of the Study:

• To investigate the role of anti-apoptotic BCL2 family members in difficult-to-treat melanomas.
• To evaluate the efficacy of dual targeting of MCL1 and BCLXL using BH3 mimetics in melanoma models.
• To explore novel therapeutic approaches for melanoma patients with limited treatment options.

Main Methods:

• Utilized genetic knockdown and pharmacologic approaches with BH3 mimetics to target MCL1 and BCLXL.
• Employed clinical-trial-ready compounds ABT-263 (Navitoclax) and S63845/S64315 (MIK655).
• Tested efficacy in melanoma cell lines from difficult-to-treat cases, in vitro assays (including sphere assays), and a mouse xenograft model.

Main Results:

• Combined inhibition of MCL1 and BCLXL demonstrated significantly effective cell killing in vitro compared to single-agent treatments (p < 0.05).
• Combination-induced cell death was independent of BIM and NOXA.
• In vivo, the dual targeting inhibited tumor growth and reduced sphere-forming capacity in a mouse xenograft model with tolerable toxicity.

Conclusions:

• MCL1 and BCLXL are crucial pro-survival members in melanoma.
• Dual targeting of MCL1 and BCLXL with BH3 mimetics is a potent strategy for difficult-to-treat melanoma.
• This approach warrants consideration as a treatment option for patients with refractory or relapsed melanoma.