Journal
ONCOTARGET
Volume 7, Issue 3, Pages 3068-3083Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6585
Keywords
lung cancer; HER3 kinase mutation; HER inhibitor; HER3-V855A
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Funding
- National Cancer Plan (Belgium) [29-039]
- Stichting Tegen Kanker (Belgium)
- Vrije Universiteit Brussel PhD fellowship
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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.
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