Abstract
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.
Highlights
Introduction The BCL2 family of proteins plays a crucial role in regulating cell death
Many studies demonstrate that several anti-apoptotic BCL-2 family members need to be targeted to kill various solid tumors; MCL-1 has emerged as a fundamental target[24,25]
We evaluated the efficacy of combining two BH3 mimetics, A-1210477 plus ABT-263, as an alternative treatment option in melanoma
Summary
Introduction The BCL2 family of proteins plays a crucial role in regulating cell death. Upregulation of anti-apoptotic BCL2 family members contribute to tumorigenesis, and resistance to chemotherapy and molecular-targeted therapies[1,2]. Many studies demonstrate that several anti-apoptotic BCL-2 family members need to be targeted to kill various solid tumors; MCL-1 has emerged as a fundamental target[24,25]. MCL-1 is an important anti-apoptotic protein of the BCL-2 family[1,2], whose upregulation is often associated with chemotherapeutic escape[26]. Pharmacological inhibition or downregulation of MCL-1 promotes apoptosis and/or overcome drug resistance in multiple cancers, including melanoma, making it a high-priority therapeutic target[27,28,29,30]. We have previously found that along with MCL-1, other BCL-2 family of anti-apoptotic proteins need to be inhibited to kill both non-MICs and MICs19,21,22
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