SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.
SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.
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DOI：
10.1158/0008-5472.can-12-1803
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发表时间：
2013-09-15
期刊：
影响因子：
11.2
通讯作者：
Yu D
中科院分区：
文献类型：
--
作者：
Zhang S;Huang WC;Zhang L;Zhang C;Lowery FJ;Ding Z;Guo H;Wang H;Huang S;Sahin AA;Aldape KD;Steeg PS;Yu D
Despite better control of early stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer, and we show how a Src-targeting combinatorial regimen can treat HER2+ brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients’ brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, a Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells_through the induction of cell cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat breast cancer patients suffering from brain metastasis.
