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Title: BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival.
Austin Authors: Lee, Erinna F;Harris, Tiffany J ;Tran, Sharon;Evangelista, Marco;Arulananda, Surein;John, Thomas ;Ramnac, Celeste;Hobbs, Chloe;Zhu, Haoran;Gunasingh, Gency;Segal, David;Behren, Andreas;Cebon, Jonathan S ;Dobrovic, Alexander ;Mariadason, John M ;Strasser, Andreas;Rohrbeck, Leona;Haass, Nikolas K;Herold, Marco J;Fairlie, W Douglas
Affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia
Karolinska Institute, Stockholm, Sweden..
Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
Issue Date: 24-Apr-2019 2019
Publication information: Cell death & disease 2019; 10(5): 342
Abstract: Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, though the outcomes of previous studies have been conflicting. To conclusively address this question, we tested a panel of established and early passage patient-derived cell lines against several BH3-mimetic drugs designed to target individual or subsets of pro-survival BCL-2 proteins, alone and in combination, in both 2D and 3D cell cultures. None of the drugs demonstrated significant activity as single agents, though combinations targeting MCL-1 plus BCL-XL, and to a lesser extent BCL-2, showed considerable synergistic killing activity that was elicited via both BAX and BAK. Genetic deletion of BFL-1 in cell lines that express it at relatively high levels only had minor impact on BH3-mimetic drug sensitivity, suggesting it is not a critical pro-survival protein in melanoma. Combinations of MCL-1 inhibitors with BRAF inhibitors also caused only minimal additional melanoma cell killing over each drug alone, whilst combinations with the proteasome inhibitor bortezomib was more effective in multiple cell lines. Our data show for the first time that therapies targeting specific combinations of BCL-2 pro-survival proteins, namely MCL-1 plus BCL-XL and MCL-1 plus BCL-2, could have significant benefit for the treatment of melanoma.
DOI: 10.1038/s41419-019-1568-3
ORCID: 0000-0001-5329-280X
PubMed URL: 31019203
Type: Journal Article
Appears in Collections:Journal articles

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