Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genomics

Background:

• Advanced melanoma, particularly rare subtypes like mucosal and acral melanoma, presents challenges for immune checkpoint blockade therapy, especially in patients lacking BRAF-V600E/K mutations.
• Identifying novel therapeutic targets is crucial for refractory or ineligible patient populations.

Purpose of the Study:

• To investigate the potential of BH3 mimetics targeting B-cell CLL/lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) as a therapeutic strategy for advanced melanoma.
• To evaluate the efficacy of combining a BCL2 inhibitor (ABT-199) with an MCL1 inhibitor in various melanoma subtypes, with a focus on BRAF mutation status.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) transcriptomic and proteomic data for differential expression of apoptosis molecules in melanomas with or without BRAF hotspot mutations.
• In vitro and in vivo assessment of the combination therapy using two BH3 mimetics (ABT-199 and an MCL1 inhibitor) across cutaneous, mucosal, and acral melanoma cell lines.
• Knockdown/knockout experiments to elucidate the role of pro-apoptotic BCL2 family members (BIM, NOXA, BID) in the observed cell death.

Main Results:

• Higher BCL2 expression was observed in melanomas without BRAF hotspot mutations, suggesting BCL2 inhibition as a potential therapeutic avenue.
• The combination of ABT-199 and an MCL1 inhibitor demonstrated potent cell death induction across diverse melanoma cell lines, including melanoma-initiating cells.
• This combination therapy was found to be more effective in melanoma cells lacking BRAF-V600E/K mutations.
• Knockdown/knockout studies indicated that BIM, NOXA, or BID are involved in the combination-induced apoptosis.

Conclusions:

• The combination of MCL1 and BCL2 inhibitors represents a promising therapeutic strategy for advanced melanoma, particularly for patients with BRAF wild-type or rare melanoma subtypes.
• This approach offers a potential treatment option for patients unresponsive or ineligible for current immune checkpoint blockade therapies.