Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
| Autor: | 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 |
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| Rok vydání: | 2018 |
| Předmět: |
Proto-Oncogene Proteins B-raf
F-Box-WD Repeat-Containing Protein 7 MAP Kinase Signaling System Protein Stability Glycine Down-Regulation Apoptosis Prognosis Mice HEK293 Cells Vemurafenib Drug Resistance Neoplasm Cell Line Tumor Proteolysis Animals Humans Sulfones neoplasms Melanoma Ubiquitin Thiolesterase Gene Deletion |
| Zdroj: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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