Corresponding Author: W. Michael Korn, UCSF Divisions of Gastroenterology and Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter St., Box 1387, San Francisco, CA 94115.
Mol Cancer Ther. 2013 Oct;12(10):2213-25. doi: 10.1158/1535-7163.MCT-13-0104. Epub 2013 Aug 5.
Mutations in the KRAS oncogene are dominant features in pancreatic ductal adenocarcinoma (PDA). Because KRAS itself is considered "undruggable," targeting pathways downstream of KRAS are being explored as a rational therapeutic strategy. We investigated the consequences of MAP-ERK kinase (MEK) inhibition in a large PDA cell line panel. Inhibition of MEK activated phosphoinositide 3-kinase in an EGF receptor (EGFR)-dependent fashion and combinations of MEK and EGFR inhibitors synergistically induced apoptosis. This combinatorial effect was observed in the epithelial but not mesenchymal subtype of PDA. RNA expression analysis revealed predictors of susceptibility to the combination, including E-cadherin, HER3, and the miR200-family of microRNAs, whereas expression of the transcription factor ZEB1 was associated with resistance to the drug combination. Knockdown of HER3 in epithelial-type and ZEB1 in mesenchymal-type PDA cell lines resulted in sensitization to the combination of MEK and EGFR inhibitors. Thus, our findings suggest a new, subtype-specific, and personalized therapeutic strategy for pancreatic cancer.
KRAS 基因突变是胰腺导管腺癌（PDA）的主要特征。由于 KRAS 本身被认为是“不可成药的”，因此靶向 KRAS 下游途径被作为一种合理的治疗策略进行探索。我们研究了在大型 PDA 细胞系面板中 MAP-ERK 激酶（MEK）抑制的后果。MEK 的抑制以 EGFR 依赖性的方式激活磷酸肌醇 3-激酶，并且 MEK 和 EGFR 抑制剂的组合协同诱导细胞凋亡。这种组合效应在 PDA 的上皮而不是间充质亚型中观察到。RNA 表达分析揭示了对组合敏感的预测因子，包括 E-钙黏蛋白、HER3 和 miR200 家族 microRNAs，而转录因子 ZEB1 的表达与对药物组合的耐药性相关。在上皮型和间充质型 PDA 细胞系中敲低 HER3 和 ZEB1，可使细胞对 MEK 和 EGFR 抑制剂的组合敏感。因此，我们的发现为胰腺癌提供了一种新的、基于亚型的、个性化的治疗策略。
