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Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling

Marcia R Campbell1, Ana Ruiz-Saenz2, Yuntian Zhang1

  • 1Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

Cell Reports
|February 2, 2022
PubMed

Insights

Extracellular domains of HER2 and HER3 receptors are not essential for tumor signaling in HER2-amplified cancers. Engineering receptor proximity did not inhibit constitutive HER2-HER3 signaling, revealing new therapeutic challenges.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Surface-targeting agents are effective in HER2-amplified cancers but fail to inhibit HER2-HER3 signaling.
  • Understanding HER2-HER3 signaling is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To conduct a structure-function analysis of the HER2-HER3 signaling pathway.
  • To investigate the role of extracellular domains (ECDs) in regulating HER2-HER3 signaling and tumorigenic function.

Main Methods:

  • Extensive structure-function analysis of HER2 and HER3 receptors.
  • Engineering receptor proximity using steric clash and bulk.
  • Assessing the impact on intracellular signaling and tumorigenic function.

Main Results:

  • HER2-HER3 signaling and tumorigenic function are uncoupled from ECD regulation.
  • Canonical HER3 ECD conformational changes and dimerization interface exposure are nonessential.
  • Entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling.
  • Disrupting ECD proximity did not perturb tumorigenic signaling.

Conclusions:

  • Tumorigenic signaling is independent of extracellular domain interactions and constraints.
  • Conformational flexibility and membrane undulations may allow signaling despite ECD modifications.
  • Targeting strategies must account for these unpredicted mechanisms in HER2-amplified cancers.
Keywords:
ERBB2ERBB3HER2HER2 overexpressionHER2-HER3 dimerizationHER3breast cancerpertuzumabtrastuzumab

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