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PLoS One. 2016 Aug 30;11(8):e0160924. doi: 10.1371/journal.pone.0160924. eCollection 2016.

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

Author information

1
Department of Internal Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, United States of America.
2
Department of Radiation Oncology, UAB, Birmingham, AL, United States of America.
3
HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America.
4
Department of Genetics, UAB, Birmingham, AL, United States of America.
5
UAB Department of Preventive Medicine, Birmingham, AL, United States of America.
6
UAB Department of Urology, Birmingham, AL, United States of America.
7
UAB Department of Urologic Pathology, Birmingham, AL, United States of America.
8
UAB Department of Medicine, Section of Hematology-Oncology and the UAB Comprehensive Cancer Center, Birmingham, AL, United States of America.

Abstract

Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

PMID:
27574806
PMCID:
PMC5004806
DOI:
10.1371/journal.pone.0160924
[Indexed for MEDLINE]
Free PMC Article

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