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Updated: Jun 13, 2025

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

Johanna Lilja1, Jasmin Kaivola1, James R W Conway1

  • 1Turku Bioscience Centre, University of Turku, FI-20520, Turku, Finland.

Nature Communications
|September 12, 2024
PubMed

Insights

Researchers discovered SHANK3 binds to KRAS, regulating its signaling. Disrupting this interaction causes cancer cell death, offering a new strategy for KRAS-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • KRAS oncogene mutations drive numerous lethal cancers, including pancreatic, lung, and colorectal types.
  • Activating KRAS mutations present significant challenges for developing targeted therapies.
  • Understanding KRAS interactors is crucial for identifying novel therapeutic strategies.

Purpose of the Study:

  • To identify novel interactors of the KRAS oncogene.
  • To investigate the role of SHANK3 in regulating KRAS signaling pathways.
  • To explore the therapeutic potential of targeting the SHANK3-KRAS interaction in KRAS-mutant cancers.

Main Methods:

  • Identification of SHANK3 as a KRAS interactor using biochemical assays.
  • Assessment of SHANK3's effect on KRAS downstream signaling, including MAPK/ERK pathway.
  • In vivo studies using RNA interference and nanobody-mediated disruption in mouse models of KRAS-mutant cancer.

Main Results:

  • SHANK3 directly binds to active KRAS, including mutant forms.
  • SHANK3 competes with RAF, limiting oncogenic KRAS signaling and maintaining optimal MAPK/ERK activity.
  • SHANK3 depletion leads to MAPK/ERK hyperactivation and cell death in KRAS-mutant cancer cells.
  • Targeting the SHANK3-KRAS interaction inhibits tumor growth in vivo.

Conclusions:

  • SHANK3 is a novel RAS interactor that negatively regulates oncogenic KRAS signaling.
  • SHANK3 depletion triggers excessive MAPK/ERK signaling, leading to selective cancer cell death.
  • Inhibition of the SHANK3-KRAS interaction is a promising therapeutic strategy for KRAS-mutant cancers.

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