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Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study

BACKGROUND: Melanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. Howev...

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Autores principales: Pópulo, Helena, Domingues, Beatriz, Sampaio, Cristina, Lopes, José Manuel, Soares, Paula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163970/
https://www.ncbi.nlm.nih.gov/pubmed/34079392
http://dx.doi.org/10.2147/JEP.S297831
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author Pópulo, Helena
Domingues, Beatriz
Sampaio, Cristina
Lopes, José Manuel
Soares, Paula
author_facet Pópulo, Helena
Domingues, Beatriz
Sampaio, Cristina
Lopes, José Manuel
Soares, Paula
author_sort Pópulo, Helena
collection PubMed
description BACKGROUND: Melanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. However, their improvements in overall survival were limited, due to the development of resistance. METHODS: In this work, several combinations of therapies, including the metabolic modulator DCA, were tested in melanoma cell lines, considering that MAPK and PI3K/AKT/mTOR pathways are deregulated and interconnected in melanoma and that the presence of the Warburg effect in melanoma cells may influence the response to therapy. The effect of the treatments was assessed in the proliferation and survival of melanoma cell lines with different genetic profiles. Also, the possibility to overcome resistance to the treatment with vemurafenib was tested. RESULTS: In general, higher decrease in cell viability and cell proliferation and increase in apoptosis were obtained after the combination treatments, comparing with single treatments, in all the studied cell lines. The combination of cobimetinib and everolimus appear to be the best treatment option. The BRAFV600E -vemurafenib resistant melanoma cell line showed to retain sensitivity to both everolimus and DCA. DISCUSSION AND CONCLUSION: Our results suggest that the combination of MAPK pathway inhibitors with mTOR pathway inhibitors and DCA should be considered as therapeutic options to treat melanoma patients, as the combinations potentiated the effects of each drug alone. In a cell line resistant to vemurafenib, we verified that combined MAPK inhibitors with inhibition of mTOR pathway and/or DCA metabolism modulation might constitute possible strategies in order to overcome resistance to MAPK inhibition.
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spelling pubmed-81639702021-06-01 Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study Pópulo, Helena Domingues, Beatriz Sampaio, Cristina Lopes, José Manuel Soares, Paula J Exp Pharmacol Original Research BACKGROUND: Melanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. However, their improvements in overall survival were limited, due to the development of resistance. METHODS: In this work, several combinations of therapies, including the metabolic modulator DCA, were tested in melanoma cell lines, considering that MAPK and PI3K/AKT/mTOR pathways are deregulated and interconnected in melanoma and that the presence of the Warburg effect in melanoma cells may influence the response to therapy. The effect of the treatments was assessed in the proliferation and survival of melanoma cell lines with different genetic profiles. Also, the possibility to overcome resistance to the treatment with vemurafenib was tested. RESULTS: In general, higher decrease in cell viability and cell proliferation and increase in apoptosis were obtained after the combination treatments, comparing with single treatments, in all the studied cell lines. The combination of cobimetinib and everolimus appear to be the best treatment option. The BRAFV600E -vemurafenib resistant melanoma cell line showed to retain sensitivity to both everolimus and DCA. DISCUSSION AND CONCLUSION: Our results suggest that the combination of MAPK pathway inhibitors with mTOR pathway inhibitors and DCA should be considered as therapeutic options to treat melanoma patients, as the combinations potentiated the effects of each drug alone. In a cell line resistant to vemurafenib, we verified that combined MAPK inhibitors with inhibition of mTOR pathway and/or DCA metabolism modulation might constitute possible strategies in order to overcome resistance to MAPK inhibition. Dove 2021-05-24 /pmc/articles/PMC8163970/ /pubmed/34079392 http://dx.doi.org/10.2147/JEP.S297831 Text en © 2021 Pópulo et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Pópulo, Helena
Domingues, Beatriz
Sampaio, Cristina
Lopes, José Manuel
Soares, Paula
Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
title Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
title_full Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
title_fullStr Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
title_full_unstemmed Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
title_short Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
title_sort combinatorial therapies to overcome braf/mek inhibitors resistance in melanoma cells: an in vitro study
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163970/
https://www.ncbi.nlm.nih.gov/pubmed/34079392
http://dx.doi.org/10.2147/JEP.S297831
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