Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations

フォーマット:

論文

責任表示:

Yamada, Tadaaki ; Takeuchi, Shinji ; Fujita, Naoya ; Nakamura, Akito ; Wang, Wei ; Li, Qi ; Oda, Makoto ; Mitsudomi, Tetsuya ; Yatabe, Yasushi ; Sekido, Yoshitaka ; Yoshida, Junji ; Higashiyama, Masahiko ; Noguchi, Masayuki ; Uehara, Hisanori ; Nishioka, Yasuhiko ; Sone, Saburo ; Yano, Seiji

言語:

英語

出版情報:

Nature Publishing Group, 2013-09-12

著者名:

Yamada, Tadaaki

Takeuchi, Shinji

Fujita, Naoya

Nakamura, Akito

Wang, Wei

Li, Qi

Oda, Makoto

Mitsudomi, Tetsuya

Yatabe, Yasushi

Sekido, Yoshitaka

Yoshida, Junji

Higashiyama, Masahiko

Noguchi, Masayuki

Uehara, Hisanori

Nishioka, Yasuhiko

Sone, Saburo

Yano, Seiji

続きを見る

掲載情報:

Oncogene

ISSN:

0950-9232      

巻:

32

通号:

37

開始ページ:

4427

終了ページ:

4435

バージョン:

author

概要:

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alte … ration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.Oncogene advance online publication, 8 October 2012; doi:10.1038/onc.2012.446.<br />In Press → 発行後6か月より全文を公開. 続きを見る

URL:

http://hdl.handle.net/2297/32869