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

2015; Impact Journals LLC; Volume: 7; Issue: 3 Linguagem: Inglês

10.18632/oncotarget.6585

1949-2553

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

Monoclonal and Polyclonal Antibodies Research

// Ijeoma Umelo 1,* , Amir Noeparast 1,* , Gang Chen 1 , Marleen Renard 2 , Caroline Geers 3 , Johan Vansteenkiste 4 , Philippe Giron 1 , Olivier De Wever 5 , Erik Teugels 1 and Jacques De Grève 1 1 Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Bruxelles, Belgium 2 Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium 3 Department of Pathology, UZ Brussel, Bruxelles, Belgium 4 Department of Pneumology, Universitair Ziekenhuis Leuven, Leuven, Belgium 5 Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Gent, Belgium * shared first authorship Correspondence: to Jacques De Grève , email: // Erik Teugels , email: // Keywords : lung cancer, HER3 kinase mutation, HER inhibitor, HER3-V855A Received : June 04, 2015 Accepted : November 14, 2015 Published : December 09, 2015 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.