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

Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and t...

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Autores principales: Mukherjee, Nabanita, Skees, Jenette, Todd, Kaleb J., West, Drake A., Lambert, Karoline A., Robinson, William A., Amato, Carol M., Couts, Kasey L., Van Gullick, Robert, MacBeth, Morgan, Nassar, Kelsey, Tan, Aik-Choon, Zhai, Zili, Fujita, Mayumi, Bagby, Stacey M., Dart, Chiara R., Lambert, James R., Norris, David A., Shellman, Yiqun G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280535/
https://www.ncbi.nlm.nih.gov/pubmed/32513939
http://dx.doi.org/10.1038/s41419-020-2646-2
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author Mukherjee, Nabanita
Skees, Jenette
Todd, Kaleb J.
West, Drake A.
Lambert, Karoline A.
Robinson, William A.
Amato, Carol M.
Couts, Kasey L.
Van Gullick, Robert
MacBeth, Morgan
Nassar, Kelsey
Tan, Aik-Choon
Zhai, Zili
Fujita, Mayumi
Bagby, Stacey M.
Dart, Chiara R.
Lambert, James R.
Norris, David A.
Shellman, Yiqun G.
author_facet Mukherjee, Nabanita
Skees, Jenette
Todd, Kaleb J.
West, Drake A.
Lambert, Karoline A.
Robinson, William A.
Amato, Carol M.
Couts, Kasey L.
Van Gullick, Robert
MacBeth, Morgan
Nassar, Kelsey
Tan, Aik-Choon
Zhai, Zili
Fujita, Mayumi
Bagby, Stacey M.
Dart, Chiara R.
Lambert, James R.
Norris, David A.
Shellman, Yiqun G.
author_sort Mukherjee, Nabanita
collection PubMed
description Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphere assays. The combination-induced cell death was independent of BIM, and NOXA. Recapitulated in our mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity (p < 0.01 and 0.05, respectively), and had tolerable toxicity (p > 0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.
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spelling pubmed-72805352020-06-16 MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells Mukherjee, Nabanita Skees, Jenette Todd, Kaleb J. West, Drake A. Lambert, Karoline A. Robinson, William A. Amato, Carol M. Couts, Kasey L. Van Gullick, Robert MacBeth, Morgan Nassar, Kelsey Tan, Aik-Choon Zhai, Zili Fujita, Mayumi Bagby, Stacey M. Dart, Chiara R. Lambert, James R. Norris, David A. Shellman, Yiqun G. Cell Death Dis Article Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphere assays. The combination-induced cell death was independent of BIM, and NOXA. Recapitulated in our mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity (p < 0.01 and 0.05, respectively), and had tolerable toxicity (p > 0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients. Nature Publishing Group UK 2020-06-08 /pmc/articles/PMC7280535/ /pubmed/32513939 http://dx.doi.org/10.1038/s41419-020-2646-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mukherjee, Nabanita
Skees, Jenette
Todd, Kaleb J.
West, Drake A.
Lambert, Karoline A.
Robinson, William A.
Amato, Carol M.
Couts, Kasey L.
Van Gullick, Robert
MacBeth, Morgan
Nassar, Kelsey
Tan, Aik-Choon
Zhai, Zili
Fujita, Mayumi
Bagby, Stacey M.
Dart, Chiara R.
Lambert, James R.
Norris, David A.
Shellman, Yiqun G.
MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
title MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
title_full MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
title_fullStr MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
title_full_unstemmed MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
title_short MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
title_sort mcl1 inhibitors s63845/mik665 plus navitoclax synergistically kill difficult-to-treat melanoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280535/
https://www.ncbi.nlm.nih.gov/pubmed/32513939
http://dx.doi.org/10.1038/s41419-020-2646-2
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