BH3 mimetics induce apoptosis independent of DRP-1 in melanoma

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 dru...

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Published in:	Cell death & disease 2018-09, Vol.9 (9), p.907-12, Article 907
Main Authors:	Mukherjee, Nabanita, Strosnider, Andrew, Vagher, Bay, Lambert, Karoline A, Slaven, Sarah, Robinson, William A, Amato, Carol M, Couts, Kasey L, Bemis, Judson G T, Turner, Jacqueline A, Norris, David A, Shellman, Yiqun G
Format:	Article
Language:	eng
Subjects:	Apoptosis Bcl-2 protein Bcl-x protein BIM protein Cancer Cell death Cell survival CRISPR Dynamin Genomes Immunotherapy Mcl-1 protein Melanoma Mutation Patients PD-1 protein Proteins Therapeutic applications
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Summary:	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
ISSN:	2041-4889 2041-4889