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J Natl Cancer Inst. 2018 Jun 28. doi: 10.1093/jnci/djy110. [Epub ahead of print]

Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets.

Author information

1
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
2
Pharmacology and Chemical Biology.
3
Women's Cancer Research Center, Magee-Women's Research Institute.
4
Department of Neurosurgery, National Neurosurgical Center, Beaumont Hospital, Dublin, Ireland.
5
Biostatistics, University of Pittsburgh Cancer Institute, University of Pittsburgh, PA.
6
Departments of Pathology.
7
Medicine.
8
Surgical Research, Royal College of Surgeons in Ireland, Dublin, Ireland.
9
Discipline of Surgery, School of Medicine, Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.
10
Molecular and Cellular Therapeutics.
11
Departments of Neuropathology.
12
Human Genetics.

Abstract

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.

PMID:
29961873
DOI:
10.1093/jnci/djy110

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