期刊
MOLECULAR ONCOLOGY
卷 16, 期 17, 页码 3128-3145出版社
WILEY
DOI: 10.1002/1878-0261.13220
关键词
breast cancer; Kras; mouse model; treatment adaptation
类别
资金
- Breast Cancer Research Foundation [BCRF-18-027]
- Department of Defense [W81XWH-13-1-0281]
- Ludwig Cancer Research Foundation
- CIRM Bridges award
- NIH [1S10RR02933801]
This study reports a mouse model of breast cancer that develops tumors in the absence of certain genes. The study found that tumors initially regress and enter remission upon inactivation of a specific oncogene, but most tumors later return. The study also identified epithelial-mesenchymal transition and active signaling pathways in tumors that adapt to oncogenic gene inhibition.
As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic Kras(G12D), develops breast tumors. Upon inactivation of Kras(G12D), tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of Kras(G12D) expression and return. Kras(G12D)-independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. Both Kras(G12D)-dependent and Kras(G12D)-independent tumors display a high level of genomic instability, and Kras(G12D)-independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial-mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic Kras(G12D) withdrawal in a novel Trp53(-/-) breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.
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