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

Animals Proto-Oncogene Proteins p21(ras) / genetics Humans Mice Cell Line, Tumor Female Nerve Tissue Proteins / metabolism MAP Kinase Signaling System / genetics Mutation Cell Death / genetics Neoplasms / genetics Extracellular Signal-Regulated MAP Kinases / metabolism Mice, Nude Microfilament Proteins

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
12 Sep 2024

Historique:

received: 09 12 2022

accepted: 03 09 2024

medline: 13 9 2024

pubmed: 13 9 2024

entrez: 12 9 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-52326-1 PMID: 39266533

pubmed: 39266533

doi: 10.1038/s41467-024-52326-1

pii: 10.1038/s41467-024-52326-1

doi:

Substances chimiques

Proto-Oncogene Proteins p21(ras) EC 3.6.5.2

Nerve Tissue Proteins 0

KRAS protein, human 0

Shank3 protein, mouse 0

Extracellular Signal-Regulated MAP Kinases EC 2.7.11.24

Microfilament Proteins 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

8002

Subventions

Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)

ID : 615258

Organisme : Academy of Finland (Suomen Akatemia)

ID : 364182

Informations de copyright

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