Nikolova Dessislava A, Asangani Irfan A, Nelson Laura D, Hughes Dennis P M, Siwak Doris R, Mills Gordon B, Harms Andrea, Buchholz Erika, Pilz Lothar R, Manegold Christian, Allgayer Heike
Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Medical Faculty Mannheim, University Heidelberg and DKFZ (German Cancer Research Center), Heidelberg, Germany.
Cancer Res. 2009 Mar 15;69(6):2461-70. doi: 10.1158/0008-5472.CAN-08-3236. Epub 2009 Mar 10.
Cetuximab, which blocks ligand binding to epidermal growth factor receptor (EGFR), is currently being studied as a novel treatment for non-small cell lung cancer (NSCLC). However, its mechanisms of action toward metastasis, and markers of drug sensitivity, have not been fully elucidated. This study was conducted to (a) determine the effect of Cetuximab on invasion and NSCLC-metastasis; (b) investigate urokinase-type plasminogen activator receptor (u-PAR), a major molecule promoting invasion and metastasis, as a target molecule; (c) delineate molecular mediators of Cetuximab-induced metastasis inhibition; and (d) identify biomarkers of drug sensitivity in NSCLC. Cetuximab treatment resulted in reduced growth and Matrigel invasion of H1395 and A549 NSCLC cell lines, in parallel with reduced u-PAR mRNA and protein. u-PAR down-regulation was brought about by suppressing the binding of JunD and c-Jun to u-PAR promoter motif -190/-171 in vivo, and an inhibition of MAP/ERK kinase signaling. Furthermore, Cetuximab inhibited NSCLC proliferation and metastasis to distant organs in vivo as indicated by the chicken embryo metastasis assay. Low E-cadherin and high u-PAR, but not EGFR, was associated with resistance to Cetuximab in seven NSCLC cell lines. Furthermore, siRNA knockdown of u-PAR led to a resensitization to Cetuximab. Moreover, low E-cadherin and high u-PAR was found in 63% of resected tumor tissues of NSCLC patients progressing under Cetuximab therapy. This is the first study to show u-PAR as a target and marker of sensitivity to Cetuximab, and to delineate novel mechanisms leading to metastasis suppression of NSCLC by Cetuximab.
西妥昔单抗可阻断配体与表皮生长因子受体（EGFR）的结合，目前正作为非小细胞肺癌（NSCLC）的一种新型治疗方法进行研究。然而，其对转移的作用机制以及药物敏感性标志物尚未完全阐明。本研究旨在：（a）确定西妥昔单抗对侵袭和NSCLC转移的影响；（b）研究尿激酶型纤溶酶原激活物受体（u-PAR），一种促进侵袭和转移的主要分子，作为靶分子；（c）描绘西妥昔单抗诱导转移抑制的分子介质；以及（d）识别NSCLC中药物敏感性的生物标志物。西妥昔单抗治疗导致H1395和A549 NSCLC细胞系的生长和基质胶侵袭减少，同时u-PAR mRNA和蛋白减少。u-PAR下调是通过在体内抑制JunD和c-Jun与u-PAR启动子基序-190/-171的结合以及抑制MAP/ERK激酶信号传导实现的。此外，鸡胚转移试验表明，西妥昔单抗在体内抑制NSCLC增殖和向远处器官的转移。在七个NSCLC细胞系中，低E-钙黏蛋白和高u-PAR，但不是EGFR，与对西妥昔单抗的耐药性相关。此外，u-PAR的siRNA敲低导致对西妥昔单抗重新敏感。此外，在接受西妥昔单抗治疗病情进展的NSCLC患者的63%切除肿瘤组织中发现低E-钙黏蛋白和高u-PAR。这是第一项表明u-PAR是西妥昔单抗敏感性的靶标和标志物，并描绘西妥昔单抗抑制NSCLC转移新机制的研究。
