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Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clin...

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Autores principales: Eritja, Núria, Chen, Bo-Juen, Rodríguez-Barrueco, Ruth, Santacana, Maria, Gatius, Sònia, Vidal, August, Martí, Maria Dolores, Ponce, Jordi, Bergadà, Laura, Yeramian, Andree, Encinas, Mario, Ribera, Joan, Reventós, Jaume, Boyd, Jeff, Villanueva, Alberto, Matias-Guiu, Xavier, Dolcet, Xavier, Llobet-Navàs, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361596/
https://www.ncbi.nlm.nih.gov/pubmed/28055301
http://dx.doi.org/10.1080/15548627.2016.1271512
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author Eritja, Núria
Chen, Bo-Juen
Rodríguez-Barrueco, Ruth
Santacana, Maria
Gatius, Sònia
Vidal, August
Martí, Maria Dolores
Ponce, Jordi
Bergadà, Laura
Yeramian, Andree
Encinas, Mario
Ribera, Joan
Reventós, Jaume
Boyd, Jeff
Villanueva, Alberto
Matias-Guiu, Xavier
Dolcet, Xavier
Llobet-Navàs, David
author_facet Eritja, Núria
Chen, Bo-Juen
Rodríguez-Barrueco, Ruth
Santacana, Maria
Gatius, Sònia
Vidal, August
Martí, Maria Dolores
Ponce, Jordi
Bergadà, Laura
Yeramian, Andree
Encinas, Mario
Ribera, Joan
Reventós, Jaume
Boyd, Jeff
Villanueva, Alberto
Matias-Guiu, Xavier
Dolcet, Xavier
Llobet-Navàs, David
author_sort Eritja, Núria
collection PubMed
description Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.
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spelling pubmed-53615962017-03-29 Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer Eritja, Núria Chen, Bo-Juen Rodríguez-Barrueco, Ruth Santacana, Maria Gatius, Sònia Vidal, August Martí, Maria Dolores Ponce, Jordi Bergadà, Laura Yeramian, Andree Encinas, Mario Ribera, Joan Reventós, Jaume Boyd, Jeff Villanueva, Alberto Matias-Guiu, Xavier Dolcet, Xavier Llobet-Navàs, David Autophagy Clinical Research Paper Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC. Taylor & Francis 2017-01-05 /pmc/articles/PMC5361596/ /pubmed/28055301 http://dx.doi.org/10.1080/15548627.2016.1271512 Text en © 2017 The Author(s). Published with license by Taylor & Francis http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Clinical Research Paper
Eritja, Núria
Chen, Bo-Juen
Rodríguez-Barrueco, Ruth
Santacana, Maria
Gatius, Sònia
Vidal, August
Martí, Maria Dolores
Ponce, Jordi
Bergadà, Laura
Yeramian, Andree
Encinas, Mario
Ribera, Joan
Reventós, Jaume
Boyd, Jeff
Villanueva, Alberto
Matias-Guiu, Xavier
Dolcet, Xavier
Llobet-Navàs, David
Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
title Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
title_full Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
title_fullStr Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
title_full_unstemmed Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
title_short Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
title_sort autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
topic Clinical Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361596/
https://www.ncbi.nlm.nih.gov/pubmed/28055301
http://dx.doi.org/10.1080/15548627.2016.1271512
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