Oncogenic ERBB3 Mutations in Human Cancers

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• 作者：Bijay S. Jaiswal¹ ; Noelyn M. Kljavin¹ ; Eric W. Stawiski¹ ; ⁹ ; Emily Chan² ; Chaitali Parikh¹ ; Steffen Durinck¹ ; ⁹ ; Subhra Chaudhuri¹ ; Kanan Pujara¹ ; Joseph Guillory¹ ; Kyle A. Edgar³ ; Vasantharajan Janakiraman¹ ; Rolf-Peter Scholz¹⁰ ; Krista K. Bowman⁴ ; ⁷ ; Maria Lorenzo⁸ ; Hong Li⁸ ; Jiansheng Wu⁸ ; Wenlin Yuan¹ ; Brock A. Peters¹ ; Zhengyan Kan¹ ; Jeremy Stinson¹ ; Michelle Mak¹ ; Zora Modrusan¹ ; Charles Eigenbrot⁴ ; Ron Firestein⁵ ; Howard M. Stern⁵ ; Krishnaraj Rajalingam¹⁰ ; Gabriele Schaefer⁶ ; Mark A. Merchant² ; Mark X. Sliwkowski⁶ ; Frederic J. de Sauvage¹ ; Somasekar Seshagiri¹ ; ^{sekar@gene.com}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：13 May, 2013
• 年：2013
• 卷：23
• 期：5
• 页码：603-617
• 全文大小：3670 K

文摘

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Summary

The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ¡«11 % of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in?vivo.