ArticleNature communications2024
SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Context-dependent synthetic lethality - an emerging precision therapeutic approach.Nature reviews. Cancer · 2026Review
- Signals from the bone marrow B cell niches shape pre-leukemic fate in a murine model of B cell acute lymphoblastic leukemia.Oncogene · 2026Article
- Shank3 related oligodendrocyte alterations in autism are restored by Erk pathway inhibition.Molecular psychiatry · 2026Article
- ANKRD53 is downregulated in human obesity and coordinates lipolysis with mitochondrial oxidative metabolism in adipocytes.Molecular metabolism · 2026Article
- Application of ultrasound and methylation omics detection in the diagnosis of endometrial cancer.Frontiers in oncology · 2026Article
- CRISPR-StAR enables high-resolution genetic screening in complex in vivo models.Nature biotechnology · 2025Article
- ALOXE3 expression predicts poor prognosis and modulates immune infiltration in colon adenocarcinoma.World journal of surgical oncology · 2025Article
- RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms.Journal of hematology & oncology · 2024Review
- NCAPG-mediated CDK1 promotes malignant progression of non-small cell lung cancer via ERK signaling activation.American journal of cancer research · 2024Article
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Authors and funding
22 authors.
Funding
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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