Src family kinases as novel therapeutic targets to treat breast cancer brain metastases

Siyuan Zhang, Wen Chien Huang, Lin Zhang, Chenyu Zhang, Frank J. Lowery, Zhaoxi Ding, Hua Guo, Hai Wang, Suyun Huang, Aysegul A. Sahin, Kenneth D. Aldape, Patricia S. Steeg, Dihua Yu

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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 brain metastasis in a preclinical model of breast cancer and we show how Srctargeting 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.

Original languageEnglish (US)
Pages (from-to)5764-5774
Number of pages11
JournalCancer research
Volume73
Issue number18
DOIs
StatePublished - Sep 15 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Src family kinases as novel therapeutic targets to treat breast cancer brain metastases'. Together they form a unique fingerprint.

Cite this