Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cancer Cell. 2013 May 13;23(5):603-17. doi: 10.1016/j.ccr.2013.04.012.
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.
人类表皮生长因子受体（HER）家族的酪氨酸激酶在多种癌症中失调，要么通过扩增、过表达或突变。ERBB3/HER3 是唯一具有受损激酶结构域的成员，尽管在某些癌症中扩增或过表达，但尚未报道携带致癌突变。在这里，我们报告了 ERBB3 体细胞突变在大约 11%的结肠癌和胃癌中的鉴定。我们发现 ERBB3 突变体以配体非依赖性方式转化结肠和乳腺上皮细胞。然而，突变型 ERBB3 的致癌活性依赖于具有激酶活性的 ERBB2。此外，我们发现抗 ERBB 抗体和小分子抑制剂可有效阻断体内突变型 ERBB3 介导的致癌信号和疾病进展。
