Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer

Oncotarget. 2016 Jan 19;7(3):3068-83. doi: 10.18632/oncotarget.6585.

Abstract

Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC). However, no conclusive reports have described pathogenic mutations in kinase-impaired HER3. Here, we report a case of an advanced chemotherapy-resistant NSCLC, harboring a novel HER3(V855A) somatic mutation homologous to the EGFR(L858R)activating mutation. Co-expression of HER3(V855A) and wild-type HER2 enhances ligand-induced transformation of murine and human cell lines, while HER-targeted inhibitors potently suppress mutant HER3 activity. Consistent with these observations, in silico computational modeling predicts that mutant V855A alters the kinase domain and c-terminal end of the HER3 protein. Taken together, these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation, in other cancers that more frequently carry somatic HER3 mutations.

Keywords: HER inhibitor; HER3 kinase mutation; HER3-V855A; lung cancer.

Publication types

  • Case Reports
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Antineoplastic Agents / therapeutic use*
  • Brain Neoplasms / secondary
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride / therapeutic use*
  • Genetic Predisposition to Disease
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Molecular Sequence Data
  • Mutation / genetics
  • Neuregulin-1 / metabolism
  • Phosphorylation
  • Prospective Studies
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Structure, Tertiary
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / genetics*
  • Receptor, ErbB-3 / metabolism
  • Tomography, X-Ray Computed

Substances

  • Antineoplastic Agents
  • Neuregulin-1
  • Protein Kinase Inhibitors
  • neuregulin beta
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ERBB2 protein, human
  • ERBB3 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3