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