2012年9月8日 讯 /生物谷BIOON/ --一项致力于揭示小细胞肺癌（small cell lung cancer）和非小细胞肺癌的分子差异的研究表明，PARP1和EZH2这两个位点可以作为治疗小细胞肺癌患者的潜在靶点。相关研究成果刊登在了近日的国际杂志Cancer Discovery上。
“在美国，目前小细胞肺癌患者在诊断出的肺癌患者中占到了15%的比例，病人起初对于化疗有明显反应，但是其在治疗数月后会病情复发，”研究者Lauren这样说。非小细胞肺癌（NSCLC）在过去十年间有很多种新药问世，不像NSCLC，小细胞肺癌患者目前的疗法仅仅是细胞毒性的化学疗法，由于许多靶位疗法都针对的是蛋白质来进行作用，那么如果在小细胞肺癌中如果识别出了某种蛋白高表达的话，那么我们就有可能以此为靶点来开发新药。
为了识别小细胞肺癌（small cell lung cancer）和非小细胞肺癌发病的分子差异，研究者使用一种称为反向阶段蛋白质阵列（reverse phase protein arrays）的技术，使得诱发癌症生长的200多种蛋白质进行表达。通过研究发现，小细胞肺癌和非小细胞肺癌在驱使癌症发病的很多蛋白质的表达上存在明显的差异。在小细胞肺癌中，许多DNA修复蛋白质如PARP1和癌症干细胞更新蛋白质EZH2都表现出高水平的情况。
PARP1可以作为治疗小细胞肺癌的潜在靶点，因为在乳腺癌和卵巢癌治疗中有很多临床药物是PARP的抑制剂，两种PARP抑制剂药物的使用可以明显降低小细胞肺癌的发展速度。下一步研究者的目的是检测PARP抑制剂和其它药物的联合使用是否可以具有更好的抑制小细胞肺癌发展速度的效果。（生物谷Bioon.com）
编译自：Novel Therapeutic Targets Identified for Small Cell Lung Cancer
doi:10.1158/2159-8290.CD-12-0112
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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.
