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

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Authors
Saei, A.
Palafox, M.
Benoukraf, T.
Kumari, N.
Jaynes, P.
Iyengar, P.
Muñoz Couselo, E.
Nuciforo, P.
Cortés, J.
Nötzel, C.
Kumarakulasinghe, N.
Richard, J.
Isa, Z.
Pang, B.
Guzman, M.
Siqin, Z.
Yang, H.
Tam, W.
Serra, V.
Eichhorn, Pieter
Date
2018
Type
Journal Article

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Saei, A. and Palafox, M. and Benoukraf, T. and Kumari, N. and Jaynes, P. and Iyengar, P. and Muñoz Couselo, E. et al. 2018. Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies. Journal of Experimental Medicine. 215 (7): pp. 1913-1928.
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Journal of Experimental Medicine
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School of Pharmacy and Biomedical Sciences
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Abstract

© 2018 Saei et al. 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.