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SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.
Lilja, Johanna; Kaivola, Jasmin; Conway, James R W; Vuorio, Joni; Parkkola, Hanna; Roivas, Pekka; Dibus, Michal; Chastney, Megan R; Varila, Taru; Jacquemet, Guillaume; Peuhu, Emilia; Wang, Emily; Pentikäinen, Ulla; Martinez D Posada, Itziar; Hamidi, Hellyeh; Najumudeen, Arafath K; Sansom, Owen J; Barsukov, Igor L; Abankwa, Daniel; Vattulainen, Ilpo; Salmi, Marko; Ivaska, Johanna.
Afiliação
  • Lilja J; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Kaivola J; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Conway JRW; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Vuorio J; Department of Physics, University of Helsinki, Helsinki, Finland.
  • Parkkola H; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Roivas P; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Dibus M; Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland.
  • Chastney MR; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Varila T; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Jacquemet G; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Peuhu E; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Wang E; Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, FI-20520, Turku, Finland.
  • Pentikäinen U; Turku Bioimaging, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland.
  • Martinez D Posada I; InFLAMES Research Flagship Center, Åbo Akademi University, FI-20520, Turku, Finland.
  • Hamidi H; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Najumudeen AK; Institute of Biomedicine, Cancer Research Laboratory FICAN West, University of Turku, FI-20520, Turku, Finland.
  • Sansom OJ; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Barsukov IL; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Abankwa D; Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland.
  • Vattulainen I; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Salmi M; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.
  • Ivaska J; Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
Nat Commun ; 15(1): 8002, 2024 Sep 12.
Article em En | MEDLINE | ID: mdl-39266533
ABSTRACT
The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3-KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3-KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas p21(ras) / Sistema de Sinalização das MAP Quinases / Mutação / Proteínas do Tecido Nervoso Limite: Animals / Female / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Finlândia País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas p21(ras) / Sistema de Sinalização das MAP Quinases / Mutação / Proteínas do Tecido Nervoso Limite: Animals / Female / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Finlândia País de publicação: Reino Unido