2012年9月8日 訊 /生物谷BIOON/ --一項(xiàng)致力于揭示小細(xì)胞肺癌（small cell lung cancer）和非小細(xì)胞肺癌的分子差異的研究表明，PARP1和EZH2這兩個(gè)位點(diǎn)可以作為治療小細(xì)胞肺癌患者的潛在靶點(diǎn),。相關(guān)研究成果刊登在了近日的國際雜志Cancer Discovery上,。
“在美國,，目前小細(xì)胞肺癌患者在診斷出的肺癌患者中占到了15%的比例，病人起初對(duì)于化療有明顯反應(yīng),，但是其在治療數(shù)月后會(huì)病情復(fù)發(fā),，”研究者Lauren這樣說。非小細(xì)胞肺癌（NSCLC）在過去十年間有很多種新藥問世,，不像NSCLC,，小細(xì)胞肺癌患者目前的療法僅僅是細(xì)胞毒性的化學(xué)療法，由于許多靶位療法都針對(duì)的是蛋白質(zhì)來進(jìn)行作用,，那么如果在小細(xì)胞肺癌中如果識(shí)別出了某種蛋白高表達(dá)的話,，那么我們就有可能以此為靶點(diǎn)來開發(fā)新藥。
為了識(shí)別小細(xì)胞肺癌（small cell lung cancer）和非小細(xì)胞肺癌發(fā)病的分子差異,，研究者使用一種稱為反向階段蛋白質(zhì)陣列（reverse phase protein arrays）的技術(shù)，使得誘發(fā)癌癥生長的200多種蛋白質(zhì)進(jìn)行表達(dá),。通過研究發(fā)現(xiàn),，小細(xì)胞肺癌和非小細(xì)胞肺癌在驅(qū)使癌癥發(fā)病的很多蛋白質(zhì)的表達(dá)上存在明顯的差異。在小細(xì)胞肺癌中,，許多DNA修復(fù)蛋白質(zhì)如PARP1和癌癥干細(xì)胞更新蛋白質(zhì)EZH2都表現(xiàn)出高水平的情況,。
PARP1可以作為治療小細(xì)胞肺癌的潛在靶點(diǎn),，因?yàn)樵谌橄侔┖吐殉舶┲委熤杏泻芏嗯R床藥物是PARP的抑制劑，兩種PARP抑制劑藥物的使用可以明顯降低小細(xì)胞肺癌的發(fā)展速度,。下一步研究者的目的是檢測(cè)PARP抑制劑和其它藥物的聯(lián)合使用是否可以具有更好的抑制小細(xì)胞肺癌發(fā)展速度的效果,。（生物谷Bioon.com）
編譯自：Novel Therapeutic Targets Identified for Small Cell Lung Cancer
doi:10.1158/2159-8290.CD-12-0112
PMC:
PMID:
Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Lauren Averett Byers1, Jing Wang2, Monique B. Nilsson1, Junya Fujimoto3, Pierre Saintigny1, John Yordy4, Uma Giri1, Michael Peyton7, You Hong Fan1, Lixia Diao2, Fatemeh Masrorpour1, Li Shen2, Wenbin Liu2, Boris Duchemann1, Praveen Tumula1, Vikas Bhardwaj4, James Welsh4, Stephanie Weber7, Bonnie S. Glisson1, Neda Kalhor3, Ignacio I. Wistuba3, Luc Girard7, Scott M. Lippman1, Gordon B. Mills5, Kevin R. Coombes2, John N. Weinstein2, John D. Minna7 and John V. Heymach1,6
Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.
