一個由美國麻省綜合醫(yī)院癌癥中心和Dana-Farber癌癥研究所的研究人員領導的國際研究隊伍發(fā)現了一些肺臟腫瘤對治療藥物如Iressa和Tarceva產生抗性的一種新途徑。這項研究的結果發(fā)表在最新一期的《科學》雜志的網站上,。該文章描述了一種可能在多種類型癌癥中都存在的一種全新抗性機制,。
研究人員發(fā)現大約20％的對Tarceva或Iressa產生抗性的腫瘤患者，其抗性是由一種癌基因的遺傳活化造成,，而這種基因卻不是這些藥物的通常靶標——這一點在之前從來沒有注意過,。
更重要的是，研究人員還確定出了對付這些抗性腫瘤的一種很有潛力的方法,，即聯合使用能直接靶向兩種蛋白質靶標的藥物,。
Iressa等藥物常用于治療晚期非小細胞肺癌。這些藥物通過抑制表皮生長因子受體（EGFR）起作用,。2004年,，麻省醫(yī)院和Danna-Farber的研究人員發(fā)現，只有EGFR基因突變放大細胞對生長因子反應的腫瘤才對這些藥物治療起反應,。
為了找到未知的抗性產生原因,，研究人員在實驗室中模擬了肺癌患者體內發(fā)生的情況。他們利用對EGFR突變敏化的肺癌細胞系,，研究了EGFR控制的細胞信號途徑,。在早期的研究中，研究人員發(fā)現以EGFR開頭的生長信號通過一種相關蛋白起作用,，這種蛋白叫做ERBB3,。
這項新的研究則證實，在一些抗性細胞中,，ERBB3蛋白因一種不同的癌基因MET的擴增而被活化——這是抑制EGFR以外的途徑,。對患者腫瘤樣本的分析顯示，MET基因在18個抗性腫瘤患者中的4個患者樣本中被擴增,。盡管單獨用Iressa或一種MET抑制劑單獨處理細胞系是不能阻止腫瘤的生長的,，但是同時使用這兩種物質則能夠誘導這些細胞死亡。
原始出處:
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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.
