期刊
ONCOTARGET
卷 7, 期 3, 页码 3068-3083出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6585
关键词
lung cancer; HER3 kinase mutation; HER inhibitor; HER3-V855A
资金
- National Cancer Plan (Belgium) [29-039]
- Stichting Tegen Kanker (Belgium)
- Vrije Universiteit Brussel PhD fellowship
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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