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

Ijeoma Umelo, Amir Noeparast, Gang Chen, Marleen Renard, Caroline Geers, Johan Vansteenkiste, Philippe Giron, Olivier De Wever, Erik Teugels, Jacques De Grève

Journal: Oncotarget 2016;7(3):3068-83

PMID: 26689995

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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.

Address: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium.; Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium.; Department of Pathology, UZ Brussel, Bruxelles, Belgium.; Department of Pneumology, Universitair Ziekenhuis Leuven, Leuven, Belgium.; Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Gent, Belgium.

DOI: 10.18632/oncotarget.6585