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Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies

RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of...

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Autores principales: Saei, Azad, Palafox, Marta, Benoukraf, Touati, Kumari, Nishi, Jaynes, Patrick William, Iyengar, Prasanna Vasudevan, Muñoz-Couselo, Eva, Nuciforo, Paolo, Cortés, Javier, Nötzel, Christopher, Kumarakulasinghe, Nesaretnam Barr, Richard, John Lalith Charles, Bin Adam Isa, Zul Fazreen, Pang, Brendan, Guzman, Marta, Siqin, Zhou, Yang, Henry, Tam, Wai Leong, Serra, Violeta, Eichhorn, Pieter Johan Adam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028519/
https://www.ncbi.nlm.nih.gov/pubmed/29880484
http://dx.doi.org/10.1084/jem.20171960
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author Saei, Azad
Palafox, Marta
Benoukraf, Touati
Kumari, Nishi
Jaynes, Patrick William
Iyengar, Prasanna Vasudevan
Muñoz-Couselo, Eva
Nuciforo, Paolo
Cortés, Javier
Nötzel, Christopher
Kumarakulasinghe, Nesaretnam Barr
Richard, John Lalith Charles
Bin Adam Isa, Zul Fazreen
Pang, Brendan
Guzman, Marta
Siqin, Zhou
Yang, Henry
Tam, Wai Leong
Serra, Violeta
Eichhorn, Pieter Johan Adam
author_facet Saei, Azad
Palafox, Marta
Benoukraf, Touati
Kumari, Nishi
Jaynes, Patrick William
Iyengar, Prasanna Vasudevan
Muñoz-Couselo, Eva
Nuciforo, Paolo
Cortés, Javier
Nötzel, Christopher
Kumarakulasinghe, Nesaretnam Barr
Richard, John Lalith Charles
Bin Adam Isa, Zul Fazreen
Pang, Brendan
Guzman, Marta
Siqin, Zhou
Yang, Henry
Tam, Wai Leong
Serra, Violeta
Eichhorn, Pieter Johan Adam
author_sort Saei, Azad
collection PubMed
description RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
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spelling pubmed-60285192018-07-05 Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies Saei, Azad Palafox, Marta Benoukraf, Touati Kumari, Nishi Jaynes, Patrick William Iyengar, Prasanna Vasudevan Muñoz-Couselo, Eva Nuciforo, Paolo Cortés, Javier Nötzel, Christopher Kumarakulasinghe, Nesaretnam Barr Richard, John Lalith Charles Bin Adam Isa, Zul Fazreen Pang, Brendan Guzman, Marta Siqin, Zhou Yang, Henry Tam, Wai Leong Serra, Violeta Eichhorn, Pieter Johan Adam J Exp Med Research Articles RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance. Rockefeller University Press 2018-07-02 /pmc/articles/PMC6028519/ /pubmed/29880484 http://dx.doi.org/10.1084/jem.20171960 Text en © 2018 Saei et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Saei, Azad
Palafox, Marta
Benoukraf, Touati
Kumari, Nishi
Jaynes, Patrick William
Iyengar, Prasanna Vasudevan
Muñoz-Couselo, Eva
Nuciforo, Paolo
Cortés, Javier
Nötzel, Christopher
Kumarakulasinghe, Nesaretnam Barr
Richard, John Lalith Charles
Bin Adam Isa, Zul Fazreen
Pang, Brendan
Guzman, Marta
Siqin, Zhou
Yang, Henry
Tam, Wai Leong
Serra, Violeta
Eichhorn, Pieter Johan Adam
Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
title Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
title_full Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
title_fullStr Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
title_full_unstemmed Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
title_short Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
title_sort loss of usp28-mediated braf degradation drives resistance to raf cancer therapies
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028519/
https://www.ncbi.nlm.nih.gov/pubmed/29880484
http://dx.doi.org/10.1084/jem.20171960
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