Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis.
2011
Purpose: Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested
pazopanib, a recently approved antiangiogenic drug that targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, PDGFRα, and c-kit, for prevention of experimental brain metastases and mechanism of action. Experimental Design: In vitro assays included B-Raf enzymatic assays, Western blots, and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or
pazopanibbeginning on day 3 postinjection. Brain metastases were counted histologically, imaged, and immunostained. Results: Treatment with 100 mg/kg of
pazopanibresulted in a 73% decline in large 231-BR-HER2 metastases ( P P = 0.004). In vitro ,
pazopanibwas directly antiproliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that
pazopanibdirectly inhibited the wild type and exon 11 oncogenic mutant, but not the
V600Emutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in
pazopanib-treated brain metastases whereas blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental
brain metastasismodel,
pazopanibreduced overall
brain metastasisvolume upon magnetic resonance imaging (MRI) by 55% ( P = 0.067), without affecting
brain metastasisvascular density. Conclusions: The data identify a new activity for
pazopanibdirectly on tumor cells as a pan-Raf inhibitor and suggest its potential for prevention of brain metastatic colonization of HER2 + breast cancer. Clin Cancer Res; 17(1); 142–53. ©2010 AACR .
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