一個(gè)由美國(guó)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(lǐng)導(dǎo)的國(guó)際研究隊(duì)伍發(fā)現(xiàn)了一些肺臟腫瘤對(duì)治療藥物如Iressa和Tarceva產(chǎn)生抗性的一種新途徑,。這項(xiàng)研究的結(jié)果發(fā)表在最新一期的《科學(xué)》雜志的網(wǎng)站上。該文章描述了一種可能在多種類(lèi)型癌癥中都存在的一種全新抗性機(jī)制,。
研究人員發(fā)現(xiàn)大約20％的對(duì)Tarceva或Iressa產(chǎn)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(biāo)——這一點(diǎn)在之前從來(lái)沒(méi)有注意過(guò),。
更重要的是,，研究人員還確定出了對(duì)付這些抗性腫瘤的一種很有潛力的方法，即聯(lián)合使用能直接靶向兩種蛋白質(zhì)靶標(biāo)的藥物,。
Iressa等藥物常用于治療晚期非小細(xì)胞肺癌,。這些藥物通過(guò)抑制表皮生長(zhǎng)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(xiàn),，只有EGFR基因突變放大細(xì)胞對(duì)生長(zhǎng)因子反應(yīng)的腫瘤才對(duì)這些藥物治療起反應(yīng)。
為了找到未知的抗性產(chǎn)生原因,，研究人員在實(shí)驗(yàn)室中模擬了肺癌患者體內(nèi)發(fā)生的情況,。他們利用對(duì)EGFR突變敏化的肺癌細(xì)胞系，研究了EGFR控制的細(xì)胞信號(hào)途徑,。在早期的研究中,，研究人員發(fā)現(xiàn)以EGFR開(kāi)頭的生長(zhǎng)信號(hào)通過(guò)一種相關(guān)蛋白起作用，這種蛋白叫做ERBB3,。
這項(xiàng)新的研究則證實(shí),，在一些抗性細(xì)胞中，ERBB3蛋白因一種不同的癌基因MET的擴(kuò)增而被活化——這是抑制EGFR以外的途徑,。對(duì)患者腫瘤樣本的分析顯示,，MET基因在18個(gè)抗性腫瘤患者中的4個(gè)患者樣本中被擴(kuò)增。盡管單獨(dú)用Iressa或一種MET抑制劑單獨(dú)處理細(xì)胞系是不能阻止腫瘤的生長(zhǎng)的,，但是同時(shí)使用這兩種物質(zhì)則能夠誘導(dǎo)這些細(xì)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.
