title: Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.
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.
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Umelo
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.
authors.forename: Amir
authors.initials: A
authors.lastname: Noeparast
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Renard
authors.affiliation: Department of Pathology, UZ Brussel, Bruxelles, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Geers
authors.affiliation: Department of Pneumology, Universitair Ziekenhuis Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vansteenkiste
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Giron
authors.affiliation: Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Gent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Teugels
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: De Grève
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020890:Neuregulin-1 / Q000378:metabolism; D010766:Phosphorylation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C117467:neuregulin beta; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: HER inhibitor; HER3 kinase mutation; HER3-V855A; lung cancer