Despite the recent advancement in treating melanoma, options are still limited 
for patients without BRAF mutations or in relapse from current treatments. BH3 
mimetics against members of the BCL-2 family have gained excitement with the 
recent success in hematological malignancies. However, single drug BH3 mimetic 
therapy in melanoma has limited effectiveness due to escape by the 
anti-apoptotic protein MCL-1 and/or survival of melanoma-initiating cells 
(MICs). We tested the efficacy of the BH3 mimetic combination of A-1210477 (an 
MCL-1 inhibitor) and ABT-263 (a BCL-2/BCL-XL/BCL-W inhibitor) in killing 
melanoma, especially MICs. We also sought to better define Dynamin-Related 
Protein 1 (DRP-1)'s role in melanoma; DRP-1 is known to interact with members of 
the BCL-2 family and is a possible therapeutic target for melanoma treatment. We 
used multiple assays (cell viability, apoptosis, bright field, immunoblot, and 
sphere formation), as well as the CRISPR/Cas9 genome-editing techniques. For 
clinical relevance, we employed patient samples of different mutation status, 
including some relapsed from current treatments such as anti-PD-1 immunotherapy. 
We found the BH3 mimetic combination kill both the MICs and non-MICs (bulk of 
melanoma) in all cell lines and patient samples irrespective of the mutation 
status or relapsed state (p < 0.05). Unexpectedly, the major pro-apoptotic 
proteins, NOXA and BIM, are not necessary for the combination-induced cell 
death. Furthermore, the combination impedes the activation of DRP-1, and 
inhibition of DRP-1 further enhances apoptosis (p < 0.05). DRP-1 effects in 
melanoma differ from those seen in other cancer cells. These results provide new 
insights into BCL-2 family's regulation of the apoptotic pathway in melanoma, 
and suggest that inhibiting the major anti-apoptotic proteins is sufficient to 
induce cell death even without involvement from major pro-apoptotic proteins. 
Importantly, our study also indicates that DRP-1 inhibition is a promising 
adjuvant for BH3 mimetics in melanoma treatment.