Please use this identifier to cite or link to this item: https://doi.org/10.1084/jem.20171960
Title: Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
Authors: Saei, A
Palafox, M
Benoukraf, T 
Kumari, N 
Jaynes, P.W 
Iyengar, P.V 
Muñoz?Couselo, E
Nuciforo, P
Cortés, J
Nötzel, C
Kumarakulasinghe, N.B
Richard, J.L.C 
Isa, Z.F.B.A 
Pang, B 
Guzman, M
Siqin, Z 
Yang, H 
Tam, W.L 
Serra, V
Eichhorn, P.J.A 
Keywords: B Raf kinase
F box/WD repeat containing protein 7
FBXW7 protein, human
glycine
rigosertib
sulfone
ubiquitin thiolesterase
USP28 protein, human
vemurafenib
analogs and derivatives
animal
apoptosis
deficiency
down regulation
drug effect
drug resistance
gene deletion
HEK293 cell line
human
MAPK signaling
melanoma
metabolism
mouse
pathology
prognosis
protein degradation
protein stability
tumor cell line
Animals
Apoptosis
Cell Line, Tumor
Down-Regulation
Drug Resistance, Neoplasm
F-Box-WD Repeat-Containing Protein 7
Gene Deletion
Glycine
HEK293 Cells
Humans
MAP Kinase Signaling System
Melanoma
Mice
Prognosis
Protein Stability
Proteolysis
Proto-Oncogene Proteins B-raf
Sulfones
Ubiquitin Thiolesterase
Vemurafenib
Issue Date: 2018
Publisher: Rockefeller University Press
Citation: Saei, A, Palafox, M, Benoukraf, T, Kumari, N, Jaynes, P.W, Iyengar, P.V, Muñoz?Couselo, E, Nuciforo, P, Cortés, J, Nötzel, C, Kumarakulasinghe, N.B, Richard, J.L.C, Isa, Z.F.B.A, Pang, B, Guzman, M, Siqin, Z, Yang, H, Tam, W.L, Serra, V, Eichhorn, P.J.A (2018). Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies. Journal of Experimental Medicine 215 (7) : 1913-1928. ScholarBank@NUS Repository. https://doi.org/10.1084/jem.20171960
Abstract: 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. © 2018 Saei et al.
Source Title: Journal of Experimental Medicine
URI: https://scholarbank.nus.edu.sg/handle/10635/175109
ISSN: 0022-1007
DOI: 10.1084/jem.20171960
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