Cargando…

Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma

The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a co...

Descripción completa

Detalles Bibliográficos
Autores principales: Vendramin, Roberto, Katopodi, Vicky, Cinque, Sonia, Konnova, Angelina, Knezevic, Zorica, Adnane, Sara, Verheyden, Yvessa, Karras, Panagiotis, Demesmaeker, Ewout, Bosisio, Francesca M., Kucera, Lukas, Rozman, Jan, Gladwyn-Ng, Ivan, Rizzotto, Lara, Dassi, Erik, Millevoi, Stefania, Bechter, Oliver, Marine, Jean-Christophe, Leucci, Eleonora
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424468/
https://www.ncbi.nlm.nih.gov/pubmed/34287642
http://dx.doi.org/10.1084/jem.20210571
_version_ 1783749682870091776
author Vendramin, Roberto
Katopodi, Vicky
Cinque, Sonia
Konnova, Angelina
Knezevic, Zorica
Adnane, Sara
Verheyden, Yvessa
Karras, Panagiotis
Demesmaeker, Ewout
Bosisio, Francesca M.
Kucera, Lukas
Rozman, Jan
Gladwyn-Ng, Ivan
Rizzotto, Lara
Dassi, Erik
Millevoi, Stefania
Bechter, Oliver
Marine, Jean-Christophe
Leucci, Eleonora
author_facet Vendramin, Roberto
Katopodi, Vicky
Cinque, Sonia
Konnova, Angelina
Knezevic, Zorica
Adnane, Sara
Verheyden, Yvessa
Karras, Panagiotis
Demesmaeker, Ewout
Bosisio, Francesca M.
Kucera, Lukas
Rozman, Jan
Gladwyn-Ng, Ivan
Rizzotto, Lara
Dassi, Erik
Millevoi, Stefania
Bechter, Oliver
Marine, Jean-Christophe
Leucci, Eleonora
author_sort Vendramin, Roberto
collection PubMed
description The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAF(V600E) melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors.
format Online
Article
Text
id pubmed-8424468
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-84244682022-03-06 Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma Vendramin, Roberto Katopodi, Vicky Cinque, Sonia Konnova, Angelina Knezevic, Zorica Adnane, Sara Verheyden, Yvessa Karras, Panagiotis Demesmaeker, Ewout Bosisio, Francesca M. Kucera, Lukas Rozman, Jan Gladwyn-Ng, Ivan Rizzotto, Lara Dassi, Erik Millevoi, Stefania Bechter, Oliver Marine, Jean-Christophe Leucci, Eleonora J Exp Med Article The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAF(V600E) melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors. Rockefeller University Press 2021-07-21 /pmc/articles/PMC8424468/ /pubmed/34287642 http://dx.doi.org/10.1084/jem.20210571 Text en © 2021 Vendramin et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Vendramin, Roberto
Katopodi, Vicky
Cinque, Sonia
Konnova, Angelina
Knezevic, Zorica
Adnane, Sara
Verheyden, Yvessa
Karras, Panagiotis
Demesmaeker, Ewout
Bosisio, Francesca M.
Kucera, Lukas
Rozman, Jan
Gladwyn-Ng, Ivan
Rizzotto, Lara
Dassi, Erik
Millevoi, Stefania
Bechter, Oliver
Marine, Jean-Christophe
Leucci, Eleonora
Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
title Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
title_full Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
title_fullStr Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
title_full_unstemmed Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
title_short Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
title_sort activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424468/
https://www.ncbi.nlm.nih.gov/pubmed/34287642
http://dx.doi.org/10.1084/jem.20210571
work_keys_str_mv AT vendraminroberto activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT katopodivicky activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT cinquesonia activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT konnovaangelina activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT knezeviczorica activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT adnanesara activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT verheydenyvessa activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT karraspanagiotis activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT demesmaekerewout activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT bosisiofrancescam activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT kuceralukas activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT rozmanjan activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT gladwynngivan activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT rizzottolara activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT dassierik activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT millevoistefania activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT bechteroliver activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT marinejeanchristophe activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma
AT leuccieleonora activationoftheintegratedstressresponseconfersvulnerabilitytomitoribosometargetingantibioticsinmelanoma