Dutt Amit, Salvesen Helga B, Chen Tzu-Hsiu, Ramos Alex H, Onofrio Robert C, Hatton Charlie, Nicoletti Richard, Winckler Wendy, Grewal Rupinder, Hanna Megan, Wyhs Nicolas, Ziaugra Liuda, Richter Daniel J, Trovik Jone, Engelsen Ingeborg B, Stefansson Ingunn M, Fennell Tim, Cibulskis Kristian, Zody Michael C, Akslen Lars A, Gabriel Stacey, Wong Kwok-Kin, Sellers William R, Meyerson Matthew, Greulich Heidi
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8713-7. doi: 10.1073/pnas.0803379105. Epub 2008 Jun 13.
Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.
酪氨酸激酶的致癌激活是癌症发生的常见机制，鉴于这些酶具有可药物作用的特性，它们是抗癌治疗中颇具吸引力的靶点。在此，我们表明，成纤维细胞生长因子受体2（FGFR2）酪氨酸激酶基因FGFR2的体细胞突变存在于12%的子宫内膜癌中，在肺鳞状细胞癌和宫颈癌中也发现了其他病例。这些FGFR2突变，其中许多与先天性颅面发育障碍相关的突变相同，在NIH 3T3细胞中异位表达时会被组成性激活并具有致癌性。在携带此类FGFR2突变的子宫内膜癌细胞系中抑制FGFR2激酶活性可抑制细胞转化和存活，这表明FGFR2是子宫内膜癌中的一个新治疗靶点。
