Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
© 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 a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal Article |
| Published: |
Rockefeller University Press
2018
|
| Online Access: | http://hdl.handle.net/20.500.11937/70928 |
| _version_ | 1848762342609780736 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Saei, A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | © 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. |
| first_indexed | 2025-11-14T10:46:03Z |
| format | Journal Article |
| id | curtin-20.500.11937-70928 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:46:03Z |
| publishDate | 2018 |
| publisher | Rockefeller University Press |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-709282018-12-13T09:33:09Z Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies 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 © 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. 2018 Journal Article http://hdl.handle.net/20.500.11937/70928 10.1084/jem.20171960 Rockefeller University Press restricted |
| spellingShingle | 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 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 |
| url | http://hdl.handle.net/20.500.11937/70928 |