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    DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

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    Type
    Article
    Authors
    Adam, Liana
    San Lucas, F Anthony
    Fowler, Jerry
    Yu, Yao
    Wu, Wenhui
    Liu, Yulun
    Wang, Huamin
    Menter, David G.
    Tetzlaff, Michael T.
    Ensor, Joe E
    Manyam, Ganiraju
    Arold, Stefan T. cc
    Huff, Chad D
    Kopetz, Scott
    Scheet, Paul
    Overman, Michael J
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
    Date
    2019-01-15
    Permanent link to this record
    http://hdl.handle.net/10754/630585
    
    Metadata
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    Abstract
    Purpose: Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease. Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays. Results: WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. While APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank hazard ratio 2.4, p=0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50<2.5nM). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, while it had no effect in an SBA wild-type ERBB2 model. Conclusions: The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbors these alterations.
    Citation
    Adam L, San Lucas FA, Fowler J, Yu Y, Wu W, et al. (2018) DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway. Clinical Cancer Research: clincanres.1480.2018. Available: http://dx.doi.org/10.1158/1078-0432.ccr-18-1480.
    Sponsors
    National Cancer Institute[P30CA16672]
    Publisher
    American Association for Cancer Research (AACR)
    Journal
    Clinical Cancer Research
    DOI
    10.1158/1078-0432.ccr-18-1480
    Additional Links
    http://clincancerres.aacrjournals.org/content/early/2018/10/23/1078-0432.CCR-18-1480
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.ccr-18-1480
    Scopus Count
    Collections
    Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

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