論文 - 詳細
| RRC ID | 67347 |
|---|---|
| 著者 | Hanker AB, Brown BP, Meiler J, Marín A, Jayanthan HS, Ye D, Lin CC, Akamatsu H, Lee KM, Chatterjee S, Sudhan DR, Servetto A, Brewer MR, Koch JP, Sheehan JH, He J, Lalani AS, Arteaga CL. |
| タイトル | Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. |
| ジャーナル | Cancer Cell |
| Abstract |
Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers. |
| 巻・号 | 39(8) |
| ページ | 1099-1114.e8 |
| 公開日 | 2021-8-9 |
| DOI | 10.1016/j.ccell.2021.06.001 |
| PII | S1535-6108(21)00284-1 |
| PMID | 34171264 |
| PMC | PMC8355076 |
| MeSH | Aminopyridines / administration & dosage Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology Breast Neoplasms / drug therapy Breast Neoplasms / genetics* Breast Neoplasms / pathology Cell Line, Tumor Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Female Gain of Function Mutation* Humans Mice, Nude Molecular Docking Simulation Molecular Dynamics Simulation Morpholines / administration & dosage Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors / administration & dosage Protein Multimerization Quinolines / administration & dosage Quinolines / chemistry Quinolines / metabolism Quinolines / pharmacology* Receptor, ErbB-2 / antagonists & inhibitors Receptor, ErbB-2 / chemistry Receptor, ErbB-2 / genetics* Receptor, ErbB-2 / metabolism Receptor, ErbB-3 / chemistry Receptor, ErbB-3 / genetics* Receptor, ErbB-3 / metabolism Trastuzumab / pharmacology Xenograft Model Antitumor Assays |
| IF | 26.602 |
| リソース情報 | |
| ヒト・動物細胞 | CW-2(RCB0778) |