دورية أكاديمية
Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets.
| العنوان: | Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets. |
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| المؤلفون: | Varešlija D; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland., Priedigkeit N; Pharmacology and Chemical Biology.; Women's Cancer Research Center, Magee-Women's Research Institute., Fagan A; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland., Purcell S; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland., Cosgrove N; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland., O'Halloran PJ; Department of Neurosurgery, National Neurosurgical Center, Beaumont Hospital, Dublin, Ireland., Ward E; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland., Cocchiglia S; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland., Hartmaier R; Pharmacology and Chemical Biology., Castro CA; Women's Cancer Research Center, Magee-Women's Research Institute., Zhu L; Biostatistics, University of Pittsburgh Cancer Institute, University of Pittsburgh, PA., Tseng GC; Biostatistics, University of Pittsburgh Cancer Institute, University of Pittsburgh, PA., Lucas PC; Departments of Pathology., Puhalla SL; Medicine., Brufsky AM; Medicine., Hamilton RL; Departments of Pathology., Mathew A; Medicine., Leone JP; Medicine., Basudan A; Pharmacology and Chemical Biology., Hudson L; Surgical Research, Royal College of Surgeons in Ireland, Dublin, Ireland., Dwyer R; Discipline of Surgery, School of Medicine, Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland., Das S; Molecular and Cellular Therapeutics., O'Connor DP; Molecular and Cellular Therapeutics., Buckley PG; Departments of Neuropathology., Farrell M; Departments of Neuropathology., Hill ADK; Surgical Research, Royal College of Surgeons in Ireland, Dublin, Ireland., Oesterreich S; Pharmacology and Chemical Biology.; Women's Cancer Research Center, Magee-Women's Research Institute., Lee AV; Pharmacology and Chemical Biology.; Human Genetics.; Women's Cancer Research Center, Magee-Women's Research Institute., Young LS; Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland. |
| المصدر: | Journal of the National Cancer Institute [J Natl Cancer Inst] 2019 Apr 01; Vol. 111 (4), pp. 388-398. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 7503089 Publication Model: Print Cited Medium: Internet ISSN: 1460-2105 (Electronic) Linking ISSN: 00278874 NLM ISO Abbreviation: J Natl Cancer Inst Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2003-> : Cary, NC : Oxford University Press Original Publication: Bethesda, Md., U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health; Washington, for sale by the Supt. of Docs., U. S. Govt. Print. Off. |
| مواضيع طبية MeSH: | Gene Expression Regulation, Neoplastic* , Transcriptome*, Biomarkers, Tumor/*genetics , Brain Neoplasms/*genetics , Breast Neoplasms/*genetics , Neoplasm Recurrence, Local/*genetics, Adult ; Animals ; Brain Neoplasms/secondary ; Breast Neoplasms/pathology ; Case-Control Studies ; Female ; Follow-Up Studies ; Gene Expression Profiling ; Humans ; Longitudinal Studies ; Mice ; Middle Aged ; Neoplasm Recurrence, Local/pathology ; Prognosis ; Survival Rate ; Xenograft Model Antitumor Assays |
| مستخلص: | Background: Breast cancer brain metastases (BrMs) are defined by complex adaptations to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly understood, as does their potential for clinical targeting. We utilized genome-wide molecular profiling to identify therapeutic targets acquired in metastatic disease. Methods: Gene expression profiling of 21 patient-matched primary breast tumors and their associated brain metastases was performed by TrueSeq RNA-sequencing to determine clinically actionable BrM target genes. Identified targets were functionally validated using small molecule inhibitors in a cohort of resected BrM ex vivo explants (n = 4) and in a patient-derived xenograft (PDX) model of BrM. All statistical tests were two-sided. Results: Considerable shifts in breast cancer cell-specific gene expression profiles were observed (1314 genes upregulated in BrM; 1702 genes downregulated in BrM; DESeq; fold change > 1.5, Padj < .05). Subsequent bioinformatic analysis for readily druggable targets revealed recurrent gains in RET expression and human epidermal growth factor receptor 2 (HER2) signaling. Small molecule inhibition of RET and HER2 in ex vivo patient BrM models (n = 4) resulted in statistically significantly reduced proliferation (P < .001 in four of four models). Furthermore, RET and HER2 inhibition in a PDX model of BrM led to a statistically significant antitumor response vs control (n = 4, % tumor growth inhibition [mean difference; SD], anti-RET = 86.3% [1176; 258.3], P < .001; anti-HER2 = 91.2% [1114; 257.9], P < .01). Conclusions: RNA-seq profiling of longitudinally collected specimens uncovered recurrent gene expression acquisitions in metastatic tumors, distinct from matched primary tumors. Critically, we identify aberrations in key oncogenic pathways and provide functional evidence for their suitability as therapeutic targets. Altogether, this study establishes recurrent, acquired vulnerabilities in BrM that warrant immediate clinical investigation and suggests paired specimen expression profiling as a compelling and underutilized strategy to identify targetable dependencies in advanced cancers. (© The Author(s) 2018. Published by Oxford University Press.) |
| التعليقات: | Erratum in: J Natl Cancer Inst. 2021 Feb 1;113(2):218. (PMID: 33099641) |
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| معلومات مُعتمدة: | T32 GM008424 United States GM NIGMS NIH HHS; F30 CA203095 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Biomarkers, Tumor) |
| تواريخ الأحداث: | Date Created: 20180703 Date Completed: 20200311 Latest Revision: 20210326 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC6449168 |
| DOI: | 10.1093/jnci/djy110 |
| PMID: | 29961873 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2105 |
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| DOI: | 10.1093/jnci/djy110 |