腫瘤通過找到另一條路徑刺激癌細胞的失控生長來擊敗針對肺癌的一種治療方法,。一類包括吉非替尼(gefitinib，商品名Iressa)和埃洛替尼(erlotinib，商品名Tarceva)的新“智能”抗癌藥物被用來治療肺癌,，該類藥物抑制癌細胞的生長,。然而，幾乎是不可避免的,，這些腫瘤對藥物產(chǎn)生了抗藥性,，又開始重新生長,。Jeff  Engelman和一個國際小組研究了針對gefitinib的抗藥性，發(fā)現(xiàn)一組癌癥復發(fā)的患者中,，一個與以前相同的細胞信號發(fā)生通道被激活,，但通過的是一個名為MET的不同基因的擴增。這項研究也許與某些胃,、頭頸癌也有關,。

英文原文：

Published Online April 26, 2007       Science DOI: 10.1126/science.1141478
  

Reports
Submitted on February 20, 2007
Accepted on April 11, 2007

MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Jeffrey A. Engelman 1, Kreshnik Zejnullahu 2, Tetsuya Mitsudomi 3, Youngchul Song 4, Courtney Hyland 5, Joon Oh Park 2, Neal Lindeman 5, Christopher-Michael Gale 6, Xiaojun Zhao 7, James Christensen 8, Takayuki Kosaka 3, Alison J. Holmes 2, Andrew M. Rogers 7, Federico Cappuzzo 9, Tony Mok 10, Charles Lee 5, Bruce E. Johnson 2, Lewis C. Cantley 4, Pasi A. Jänne 2*
1 Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
2 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
4 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
5 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
6 Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
8 Pfizer Global Research and Development, Department of Research Pharmacology, La Jolla Labs, La Jolla, CA 92121, USA.
9 Istituto Clinico Humanitas, Department on Hematology-Oncology, Rozzano 20089, Italy.
10 Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.

* To whom correspondence should be addressed.
Pasi A. Jänne , E-mail: [email protected]

Abstract

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are used clinically for the treatment of lung cancers with EGFR activating mutations, but the tumors invariably develop drug resistance. To investigate resistance mechanisms, we isolated gefitinib-resistant clones from an EGFR mutant lung cancer cell line. The resistant cells displayed amplification of the MET oncogene and maintained activation of ERBB3/PI3K/Akt signaling in the presence of gefitinib. Inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 out of 18 (22%) lung cancer specimens that had become resistant to gefitinib or erlotinib. Because amplified MET activates the ERBB3/PI3K pathway in other tumor cell lines, our results raise the possibility that MET amplification promotes drug resistance in other ERBB-driven cancers.