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PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma

BACKGROUND: Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying ke...

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Autores principales: Corrales, Eyleen, Levit-Zerdoun, Ella, Metzger, Patrick, Mertes, Ralf, Lehmann, Ariane, Münch, Julia, Lemke, Steffen, Kowar, Silke, Boerries, Melanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700886/
https://www.ncbi.nlm.nih.gov/pubmed/36434616
http://dx.doi.org/10.1186/s12964-022-00989-y
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author Corrales, Eyleen
Levit-Zerdoun, Ella
Metzger, Patrick
Mertes, Ralf
Lehmann, Ariane
Münch, Julia
Lemke, Steffen
Kowar, Silke
Boerries, Melanie
author_facet Corrales, Eyleen
Levit-Zerdoun, Ella
Metzger, Patrick
Mertes, Ralf
Lehmann, Ariane
Münch, Julia
Lemke, Steffen
Kowar, Silke
Boerries, Melanie
author_sort Corrales, Eyleen
collection PubMed
description BACKGROUND: Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies. METHODS: We performed a comprehensive molecular and phenotypic characterization of a panel of patient-derived BRAF(V600E)-positive melanoma cell lines. Transcriptional profiling was used to identify groups of coregulated genes whose expression relates to an increased migratory potential and a higher resistance. RESULTS: A decrease in sensitivity to MAPK/ERK pathway inhibition with vemurafenib or trametinib corresponded with an increasing quiescence and migratory properties of the cells. This was accompanied by the loss of transcriptional signatures of melanocytic differentiation, and the gain of stem cell features that conferred highly-resistant/mesenchymal-like cells with increased xenobiotic efflux capacity. Nevertheless, targeting of the implicated ABC transporters did not improve the response to vemurafenib, indicating that incomplete BRAF inhibition due to reduced drug uptake is not a main driver of resistance. Rather, indifference to MAPK/ERK pathway inhibition arose from the activation of compensatory signaling cascades. The PI3K/AKT pathway in particular showed a higher activity in mesenchymal-like cells, conferring a lower dependency on MAPK/ERK signaling and supporting stem-like properties that could be reverted by dual PI3K/mTOR inhibition with dactolisib. CONCLUSIONS: In case of MAPK/ERK independency, therapeutic focus may be shifted to the PI3K/AKT pathway to overcome late-stage resistance in melanoma tumors that have acquired a mesenchymal phenotype. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00989-y.
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spelling pubmed-97008862022-11-27 PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma Corrales, Eyleen Levit-Zerdoun, Ella Metzger, Patrick Mertes, Ralf Lehmann, Ariane Münch, Julia Lemke, Steffen Kowar, Silke Boerries, Melanie Cell Commun Signal Research BACKGROUND: Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies. METHODS: We performed a comprehensive molecular and phenotypic characterization of a panel of patient-derived BRAF(V600E)-positive melanoma cell lines. Transcriptional profiling was used to identify groups of coregulated genes whose expression relates to an increased migratory potential and a higher resistance. RESULTS: A decrease in sensitivity to MAPK/ERK pathway inhibition with vemurafenib or trametinib corresponded with an increasing quiescence and migratory properties of the cells. This was accompanied by the loss of transcriptional signatures of melanocytic differentiation, and the gain of stem cell features that conferred highly-resistant/mesenchymal-like cells with increased xenobiotic efflux capacity. Nevertheless, targeting of the implicated ABC transporters did not improve the response to vemurafenib, indicating that incomplete BRAF inhibition due to reduced drug uptake is not a main driver of resistance. Rather, indifference to MAPK/ERK pathway inhibition arose from the activation of compensatory signaling cascades. The PI3K/AKT pathway in particular showed a higher activity in mesenchymal-like cells, conferring a lower dependency on MAPK/ERK signaling and supporting stem-like properties that could be reverted by dual PI3K/mTOR inhibition with dactolisib. CONCLUSIONS: In case of MAPK/ERK independency, therapeutic focus may be shifted to the PI3K/AKT pathway to overcome late-stage resistance in melanoma tumors that have acquired a mesenchymal phenotype. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00989-y. BioMed Central 2022-11-24 /pmc/articles/PMC9700886/ /pubmed/36434616 http://dx.doi.org/10.1186/s12964-022-00989-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Corrales, Eyleen
Levit-Zerdoun, Ella
Metzger, Patrick
Mertes, Ralf
Lehmann, Ariane
Münch, Julia
Lemke, Steffen
Kowar, Silke
Boerries, Melanie
PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
title PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
title_full PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
title_fullStr PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
title_full_unstemmed PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
title_short PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
title_sort pi3k/akt signaling allows for mapk/erk pathway independency mediating dedifferentiation-driven treatment resistance in melanoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700886/
https://www.ncbi.nlm.nih.gov/pubmed/36434616
http://dx.doi.org/10.1186/s12964-022-00989-y
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