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Src Family Kinases as Novel Therapeutic Targets to Treat Breast Cancer Brain Metastases.
- Source :
-
Cancer Research . Sep2013, Vol. 73 Issue 18, p5764-5774. 11p. - Publication Year :
- 2013
-
Abstract
- 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 brainmetastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens 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, an 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 patients with breast cancer suffering from brain metastasis. [ABSTRACT FROM AUTHOR]
- Subjects :
- *BREAST cancer treatment
*CANCER invasiveness
*CELL lines
*BRAIN cancer
*CELL cycle
Subjects
Details
- Language :
- English
- ISSN :
- 00085472
- Volume :
- 73
- Issue :
- 18
- Database :
- Academic Search Index
- Journal :
- Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 91875418
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-12-1803