Science：癌症药物抗性的关键基因

生物谷

    一个由美国麻省综合医院癌症中心和Dana-Farber癌症研究所的研究人员领导的国际研究队伍发现了一些肺脏肿瘤对治疗药物如Iressa和Tarceva产生抗性的一种新途径。这项研究的结果发表在最新一期的《科学》杂志的网站上。该文章描述了一种可能在多种类型癌症中都存在的一种全新抗性机制。

    研究人员发现大约20％的对Tarceva或Iressa产生抗性的肿瘤患者，其抗性是由一种癌基因的遗传活化造成，而这种基因却不是这些药物的通常靶标——这一点在之前从来没有注意过。

    更重要的是，研究人员还确定出了对付这些抗性肿瘤的一种很有潜力的方法，即联合使用能直接靶向两种蛋白质靶标的药物。

    Iressa等药物常用于治疗晚期非小细胞肺癌。这些药物通过抑制表皮生长因子受体（EGFR）起作用。2004年，麻省医院和Danna-Farber的研究人员发现，只有EGFR基因突变放大细胞对生长因子反应的肿瘤才对这些药物治疗起反应。

    为了找到未知的抗性产生原因，研究人员在实验室中模拟了肺癌患者体内发生的情况。他们利用对EGFR突变敏化的肺癌细胞系，研究了EGFR控制的细胞信号途径。在早期的研究中，研究人员发现以EGFR开头的生长信号通过一种相关蛋白起作用，这种蛋白叫做ERBB3。

    这项新的研究则证实，在一些抗性细胞中，ERBB3蛋白因一种不同的癌基因MET的扩增而被活化——这是抑制EGFR以外的途径。对患者肿瘤样本的分析显示，MET基因在18个抗性肿瘤患者中的4个患者样本中被扩增。尽管单独用Iressa或一种MET抑制剂单独处理细胞系是不能阻止肿瘤的生长的，但是同时使用这两种物质则能够诱导这些细胞死亡。

原始出处:

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.

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