Jimeno Antonio, Tan Aik Choon, Coffa Jordy, Rajeshkumar N V, Kulesza Peter, Rubio-Viqueira Belen, Wheelhouse Jenna, Diosdado Begoña, Messersmith Wells A, Iacobuzio-Donahue Christine, Maitra Anirban, Varella-Garcia Marileila, Hirsch Fred R, Meijer Gerrit A, Hidalgo Manuel
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231-1000, USA.
Cancer Res. 2008 Apr 15;68(8):2841-9. doi: 10.1158/0008-5472.CAN-07-5200.
The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development.
表皮生长因子受体（EGFR）抑制剂厄洛替尼已被批准用于治疗胰腺癌，但总体活性极小，且在该疾病中已知的EGFR抑制剂疗效预测因素并不常见。我们检验了EGFR通路的整体激活可预测EGFR抑制剂疗效这一假说。对手术时直接异种移植的胰腺癌肿瘤用EGFR抑制剂厄洛替尼和西妥昔单抗进行治疗，并分析其生物学特征。10个肿瘤中有2个敏感，通过基因集富集分析的全基因组表达谱分析，与耐药肿瘤相比，敏感肿瘤中EGFR通路高度表达。驱动EGFR通路过表达的核心基因成分是通路配体和正向效应器。在一项前瞻性验证中，基于EGFR通路的特征正确预测了另外8个肿瘤的抗EGFR治疗反应，且不能预测对吉西他滨和CI1040（一种MEK抑制剂）的反应。通过荧光原位杂交和多重连接依赖探针扩增对EGFR、KRAS和PIK3CA突变及基因扩增进行分析，结果显示这些基因异常均不能预测EGFR通路激活，也与EGFR通路激活无关。EGFR通路的协同过表达可预测胰腺癌对EGFR抑制剂的敏感性。这些结果提示了一种通路成瘾现象，并支持了无偏系统生物学方法在药物开发中的价值。
