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SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers

Author

Listed:
  • Johanna Lilja

    (University of Turku)

  • Jasmin Kaivola

    (University of Turku)

  • James R. W. Conway

    (University of Turku)

  • Joni Vuorio

    (University of Helsinki)

  • Hanna Parkkola

    (University of Turku)

  • Pekka Roivas

    (University of Turku
    University of Turku)

  • Michal Dibus

    (University of Turku)

  • Megan R. Chastney

    (University of Turku)

  • Taru Varila

    (University of Turku)

  • Guillaume Jacquemet

    (University of Turku
    Åbo Akademi University
    University of Turku and Åbo Akademi University
    Åbo Akademi University)

  • Emilia Peuhu

    (University of Turku
    University of Turku)

  • Emily Wang

    (University of Liverpool)

  • Ulla Pentikäinen

    (University of Turku
    University of Turku)

  • Itziar Martinez D. Posada

    (University of Turku)

  • Hellyeh Hamidi

    (University of Turku)

  • Arafath K. Najumudeen

    (University of Helsinki
    Garscube Estate)

  • Owen J. Sansom

    (Garscube Estate
    Garscube Estate)

  • Igor L. Barsukov

    (University of Liverpool)

  • Daniel Abankwa

    (University of Turku
    University of Luxembourg)

  • Ilpo Vattulainen

    (University of Helsinki)

  • Marko Salmi

    (University of Turku
    University of Turku
    University of Turku)

  • Johanna Ivaska

    (University of Turku
    University of Turku
    University of Turku
    Foundation for the Finnish Cancer Institute)

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.

Suggested Citation

  • Johanna Lilja & Jasmin Kaivola & James R. W. Conway & Joni Vuorio & Hanna Parkkola & Pekka Roivas & Michal Dibus & Megan R. Chastney & Taru Varila & Guillaume Jacquemet & Emilia Peuhu & Emily Wang & U, 2024. "SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52326-1
    DOI: 10.1038/s41467-024-52326-1
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