Transcriptome characterization of matched primary breast and brain metastatic tumors to detect novel actionable targets.
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.
Irish Cancer Society Collaborative Cancer Research Centre grant CCRC13GAL
Science Foundation Ireland Investigator Award 12/IA/1294
Breast Cancer Ireland Programme Grant
Breast Cancer Research Foundation
National Cancer Institute (NCI) of the National Institutes of Health (NIH; P30CA047904)
Fashion Footwear Association of New York (FFANY)
Nicole Meloche Memorial Breast Cancer Research Foundation
Shear Family Foundation
Magee-Womens Research Institute and Foundation
Scientific Advisory Council awards from Susan G. Komen
NIH/National Institute of General Medical Science (2T32GM008424-21)
Associated research data filesSupplementary data at publisher's website: https://doi.org/10.1093/jnci/djy110
CommentsThe original article is available at https://academic.oup.com/
Published CitationVarešlija D, Priedigkeit N, Fagan A, Purcell S, Cosgrove N, O'Halloran PJ, Ward E, Cocchiglia S, Hartmaier R, Castro CA, Zhu L, Tseng GC, Lucas PC, Puhalla SL, Brufsky AM, Hamilton RL, Mathew A, Leone JP, Basudan A, Hudson L, Dwyer R, Das S, O'Connor DP, Buckley PG, Farrell M, Hill ADK, Oesterreich S, Lee AV, Young LS. Transcriptome characterization of matched primary breast and brain metastatic tumors to detect novel actionable targets. Journal of the National Cancer Institute. 2019;111(4):388-398.
Publication Date28 June 2018
- Beaumont Hospital
- School of Pharmacy and Biomolecular Sciences
- Surgical Science and Practice
- Immunity, Infection and Inflammation
PublisherOxford University Press (OUP)
- Published Version (Version of Record)