Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
Ramkissoon, Shakti H.
Ramkissoon, Lori A.
Kang, Yun Jee
Iglehart, J. Dirk
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CitationNi, J., S. H. Ramkissoon, S. Xie, S. Goel, D. G. Stover, H. Guo, V. Luu, et al. 2016. “Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases.” Nature medicine 22 (7): 723-726. doi:10.1038/nm.4120. http://dx.doi.org/10.1038/nm.4120.
AbstractBrain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response correlated with reduction of 4EBP1 phosphorylation. The two non-responding PDXs showed hypermutated genomes with enrichment of mutations in DNA repair genes, suggesting an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor plus an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.
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