https://scholars.lib.ntu.edu.tw/handle/123456789/587143
標題: | Identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer | 作者: | Wang Y.-W Tu P.-H Lin K.-T Lin S.-C JENG-YUH KO Jou Y.-S. |
公開日期: | 2011 | 出版社: | Elsevier B.V. | 卷: | 13 | 期: | 8 | 起(迄)頁: | 704-715 | 來源出版物: | Neoplasia | 摘要: | The oncogenic property of anaplastic lymphoma kinase (ALK) plays an essential role in the pathogenesis of various cancers and serves as an important therapeutic target. In this study, we identified frequent intragenic loss of heterozygosity and six novel driver mutations within ALK in lung adenocarcinomas. Overexpression of H694R or E1384K mutant ALK leads to hyperphosphorylation of ALK, and activation of its downstream mediators STAT3, AKT, and ERK resulted in enhanced cell proliferation, colony formation, cell migration, and tumor growth in xenograft models. Furthermore, the activated phospho-Y1604 ALK was increasingly detected in 13 human lung cancer cell lines and 263 lung cancer specimens regardless of tumor stages and types. Treatment of two different ALK inhibitors, WHIP154 and NVP-TAE684, resulted in the down-regulation of aberrant ALK signaling, shrinkage of tumor, and suppression of metastasis and significantly improved survival of ALK mutant-bearing mice. Together, we identified that novel ALK point mutations possessed tumorigenic effects mainly through hyperphosphorylation of Y1604 and activation of downstream oncogenic signaling. The upregulated phospho-Y1604 ALK could serve as a diagnostic biomarker for lung cancer. Furthermore, targeting oncogenic mutant ALKs with inhibitors could be a promising strategy to improve the therapeutic efficacy of fatal lung cancers. ? 2011 Neoplasia Press, Inc. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-80051492649&doi=10.1593%2fneo.11222&partnerID=40&md5=0934c8c4bdeed5197a5095b543c30be4 https://scholars.lib.ntu.edu.tw/handle/123456789/587143 |
ISSN: | 1522-8002 | DOI: | 10.1593/neo.11222 | SDG/關鍵字: | anaplastic lymphoma kinase; mitogen activated protein kinase; protein kinase B; STAT3 protein; adult; aged; alk gene; animal experiment; animal model; article; cancer cell culture; cancer inhibition; cancer survival; cancer tissue; carcinogenicity; cell migration; cell proliferation; clinical article; colony formation; controlled study; down regulation; enzyme activation; enzyme phosphorylation; female; gene; heterozygosity loss; human; human cell; human tissue; lung adenocarcinoma; lung cancer; male; metastasis inhibition; mouse; nonhuman; point mutation; priority journal; signal transduction; tumor growth; tumor xenograft |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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