[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lilja, Johanna; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Kaivola, Jasmin ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Conway, James R W ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Vuorio, Joni ; Department of Physics, University of Helsinki, Helsinki, Finland
Parkkola, Hanna ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Roivas, Pekka; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland ; Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland
Dibus, Michal ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Chastney, Megan R ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Varila, Taru; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Jacquemet, Guillaume ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland ; Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, FI-20520, Turku, Finland ; Turku Bioimaging, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland ; InFLAMES Research Flagship Center, Åbo Akademi University, FI-20520, Turku, Finland
Peuhu, Emilia ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland ; Institute of Biomedicine, Cancer Research Laboratory FICAN West, University of Turku, FI-20520, Turku, Finland
Wang, Emily; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
Pentikäinen, Ulla; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland ; Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland
Martinez D Posada, Itziar; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Hamidi, Hellyeh ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Najumudeen, Arafath K ; Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland ; CRUK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
Sansom, Owen J ; CRUK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK ; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK
Barsukov, Igor L ; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
ABANKWA, Daniel ; University of Luxembourg ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland
Vattulainen, Ilpo ; Department of Physics, University of Helsinki, Helsinki, Finland
Salmi, Marko; Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland ; MediCity Research Laboratory, University of Turku, FI-20520, Turku, Finland ; InFLAMES Research Flagship Center, University of Turku, FI-20520, Turku, Finland
Ivaska, Johanna ; Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland. Johanna.ivaska@utu.fi ; InFLAMES Research Flagship Center, University of Turku, FI-20520, Turku, Finland. Johanna.ivaska@utu.fi ; Department of Life Technologies, University of Turku, Turku, Finland. Johanna.ivaska@utu.fi ; Foundation for the Finnish Cancer Institute, Tukholmankatu 8, FI-00014, Helsinki, Finland. Johanna.ivaska@utu.fi ; Western Finnish Cancer Center, University of Turku, Turku, FI-20520, Finland. Johanna.ivaska@utu.fi
We thank P. Laasola, J. Siivonen, E-M. Vesilahti, M. Miihkinen, S. Salomaa and A. Isomursu for technical assistance and scientific discussion, the Ivaska lab for critical reading and feedback on the manuscript and O. Pentik\u00E4inen for protein complex modelling. The Cell Imaging and Cytometry Core (Turku Bioscience Centre, University of Turku) and Turku Centre for Disease Modelling (TCDM), both supported by Biocenter Finland, the Euro-BioImaging Finnish Node (Turku Finland), the University of Turku Histocore and Genome Editing core are acknowledged for services, instrumentation, and expertise. We also gratefully acknowledge CSC \u2013 IT Center for Science (Espoo, Finland) for providing ample computing resources. This work was supported by the Research Council of Finland through the following programs: an InFLAMES Flagship Programme (337530, UTU and 337531, \u00C5bo Akademi), Research project grants (325464, J.I., and 331349, I.V.), Research Fellowships (338537 G.J. and 323096 E.P.), the CoE for Biological Barrier Mechanics and Disease (346131 & 364182, J.I., and 346135 & 364185, I.V.,). Additional funding was provided by an ERC consolidator (615258, J.I.) and a proof of concept grant (899155, J.I.), the Sigrid Juselius Foundation (J.I., G.J., E.P., and I.V.), the Finnish Cultural Foundation (J.L. and E.P), the Cancer Foundation Finland (J.I., M.S., G.J., and I.V.), the Frontier Science Program (RGP0059/2019, I.V.), the Helsinki Institute of Life Science (HiLIFE) Fellow program (I.V.), the Lundbeck Foundation (I.V.) and a Novo Nordisk pre-seed grant (J.I.). J.L., and J.K., were supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM), J.L by the Instrumentarium Foundation, the Orion Research Foundation Sr and the K. Albin Johansson Foundation, and P.R. by the Drug Research Doctoral Programme at the University of Turku. J.R.W.C. was supported by the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement [841973] and a Research Council of Finland postdoctoral research grant (338585), M.D. by the European Union\u2019s Horizon Europe research and innovation programme under Marie Sklodowska-Curie grant [101108089], M.C. by a Research Council of Finland postdoctoral research grant (343239) and AKN by CRUK Scotland Institute core funding (A17196, and A31287 - awarded to O.J.S.,). O.J.S., was supported by CRUK grants (A21139, A12481, A17196 and A31287) and an ERC Starting grant (311301).We thank P. Laasola, J. Siivonen, E-M. Vesilahti, M. Miihkinen, S. Salomaa and A. Isomursu for technical assistance and scientific discussion, the Ivaska lab for critical reading and feedback on the manuscript and O. Pentik\u00E4inen for protein complex modelling. The Cell Imaging and Cytometry Core (Turku Bioscience Centre, University of Turku) and Turku Centre for Disease Modelling (TCDM), both supported by Biocenter Finland, the Euro-BioImaging Finnish Node (Turku Finland), the University of Turku Histocore and Genome Editing core are acknowledged for services, instrumentation, and expertise. We also gratefully acknowledge CSC \u2013 IT Center for Science (Espoo, Finland) for providing ample computing resources. This work was supported by the Research Council of Finland through the following programs: an InFLAMES Flagship Programme (337530, UTU and 337531, \u00C5bo Akademi), Research project grants (325464, J.I., and 331349, I.V.), Research Fellowships (338537\u2009G.J. and 323096 E.P.), the CoE for Biological Barrier Mechanics and Disease (346131 & 364182, J.I., and 346135 & 364185, I.V.,). Additional funding was provided by an ERC consolidator (615258, J.I.) and a proof of concept grant (899155, J.I.), the Sigrid Juselius Foundation (J.I., G.J., E.P., and I.V.), the Finnish Cultural Foundation (J.L. and E.P), the Cancer Foundation Finland (J.I., M.S., G.J., and I.V.), the Frontier Science Program (RGP0059/2019, I.V.), the Helsinki Institute of Life Science (HiLIFE) Fellow program (I.V.), the Lundbeck Foundation (I.V.) and a Novo Nordisk pre-seed grant (J.I.). J.L., and J.K., were supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM), J.L by the Instrumentarium Foundation, the Orion Research Foundation Sr and the K. Albin Johansson Foundation, and P.R. by the Drug Research Doctoral Programme at the University of Turku. J.R.W.C. was supported by the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement [841973] and a Research Council of Finland postdoctoral research grant (338585), M.D. by the European Union\u2019s Horizon Europe research and innovation programme under Marie Sklodowska-Curie grant [101108089], M.C. by a Research Council of Finland postdoctoral research grant (343239) and AKN by CRUK Scotland Institute core funding (A17196, and A31287 - awarded to O.J.S.,). O.J.S., was supported by CRUK grants (A21139, A12481, A17196 and A31287) and an ERC Starting grant (311301).
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