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      Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

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      Author(s)
      Sahin, O.
      Wang, Q.
      Brady, S. W.
      Ellis, K.
      Wang, H.
      Chang, C. C.
      Zhang, Q.
      Priya, P.
      Zhu, R.
      Wong, S. T.
      Landis, M. D.
      Muller, W. J.
      Esteva, F. J.
      Chang, J.
      Yu, D.
      Date
      2014
      Source Title
      Cell Research
      Print ISSN
      1001-0602
      Publisher
      Nature Publising Group
      Volume
      24
      Issue
      5
      Pages
      542 - 559
      Language
      English
      Type
      Article
      Item Usage Stats
      108
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      86
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      Abstract
      Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by-passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.
      Keywords
      Bez235
      Erbb2 Stabilization
      Sequential Therapy
      Targeted Therapy
      Trastuzumab Resistance
      Tumor Evolution
      Permalink
      http://hdl.handle.net/11693/12616
      Published Version (Please cite this version)
      http://dx.doi.org/10.1038/cr.2014.37
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