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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.
Afiliación
  • Saei A; Genome Institute of Singapore, A*STAR, Singapore, Singapore.
  • Palafox M; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Benoukraf T; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • Kumari N; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Jaynes PW; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Iyengar PV; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Muñoz-Couselo E; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Nuciforo P; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Cortés J; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • Nötzel C; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • Kumarakulasinghe NB; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • Richard JLC; Cancer Ramon y Cajal University Hospital, Madrid, Spain.
  • Bin Adam Isa ZF; IOB Institute of Oncology, Quironsalud group, Madrid & Barcelona, Spain.
  • Pang B; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Guzman M; Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore.
  • Siqin Z; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Yang H; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Tam WL; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Serra V; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • Eichhorn PJA; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
J Exp Med ; 215(7): 1913-1928, 2018 07 02.
Article en En | MEDLINE | ID: mdl-29880484
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Ubiquitina Tiolesterasa / Proteínas Proto-Oncogénicas B-raf / Proteolisis / Melanoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Exp Med Año: 2018 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Ubiquitina Tiolesterasa / Proteínas Proto-Oncogénicas B-raf / Proteolisis / Melanoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Exp Med Año: 2018 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Estados Unidos