Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity

Ariella B. Hanker, Benjamin P. Brown, Jens Meiler, Arnaldo Marín, Harikrishna S. Jayanthan, Dan Ye, Chang Ching Lin, Hiroaki Akamatsu, Kyung Min Lee, Sumanta Chatterjee, Dhivya R. Sudhan, Alberto Servetto, Monica Red Brewer, James P. Koch, Jonathan H. Sheehan, Jie He, Alshad S. Lalani, Carlos L. Arteaga

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.

Original languageEnglish (US)
Pages (from-to)1099-1114.e8
JournalCancer Cell
Volume39
Issue number8
DOIs
StatePublished - Aug 9 2021

Keywords

  • breast cancer
  • HER2
  • HER3
  • molecular dynamics
  • neratinib
  • personalized structural biology
  • PI3K
  • precision oncology
  • Rosetta

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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