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Xie, Shaozhen

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Xie

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Shaozhen

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Xie, Shaozhen

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20162

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Author's Publications: search.filters.isAuthorOfPublication.329fe40c-a8f1-4317-9d82-db9290e0180c

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    Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss
    (eLife Sciences Publications, Ltd, 2016) Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen; Zhao, Jean; Roberts, Thomas
    We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110α and p110β. We found that p110β localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110β to rafts alleviated the requirement for p110β-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110β dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110β. DOI: http://dx.doi.org/10.7554/eLife.17635.001
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    Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
    (2016) Ni, Jing; Ramkissoon, Shakti H.; Xie, Shaozhen; Goel, Shom; Stover, Daniel G.; Guo, Hanbing; Luu, Victor; Marco, Eugenio; Ramkissoon, Lori A.; Kang, Yun Jee; Hayashi, Marika; Nguyen, Quang-De; Ligon, Azra; Du, Rose; Claus, Elizabeth; Alexander, Brian; Yuan, Guo-Cheng; Wang, Zhigang C.; Iglehart, J. Dirk; Krop, Ian; Roberts, Thomas; Winer, Eric; Lin, Nancy; Ligon, Keith; Zhao, Jean
    Brain 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.