期刊
CANCER DISCOVERY
卷 5, 期 8, 页码 832-841出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-14-1211
关键词
-
类别
资金
- NIH [R01CA161001]
- Ohana Breast Cancer Research Fund
- Foundation for Barnes-Jewish Hospital
- Fight Colorectal Cancer-AACR Career Development Award
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [9970]
- AIRC [14205, 15571]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS
- Ministero della Salute
- NATIONAL CANCER INSTITUTE [R01CA161001] Funding Source: NIH RePORTER
The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. SIGNIFICANCE: HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. (C) 2015 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据