肿瘤通过找到另一条路径刺激癌细胞的失控生长来击败针对肺癌的一种治疗方法。一类包括吉非替尼(gefitinib，商品名Iressa)和埃洛替尼(erlotinib，商品名Tarceva)的新“智能”抗癌药物被用来治疗肺癌，该类药物抑制癌细胞的生长。然而，几乎是不可避免的，这些肿瘤对药物产生了抗药性，又开始重新生长。Jeff Engelman和一个国际小组研究了针对gefitinib的抗药性，发现一组癌症复发的患者中，一个与以前相同的细胞信号发生通道被激活，但通过的是一个名为MET的不同基因的扩增。这项研究也许与某些胃、头颈癌也有关。
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: pjanne@partners.org
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.
