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

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.

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

“…integrins, heparanases, and matrix metalloproteinases) have inhibitors that are currently under study in phase I/II/III clinical trials [27][28][29][30][31][32][33]. Kinase genes have also recently been reported to be upregulated in metastatic tumors relative to primary ccRCC tumors [34]. Thus, further study is required to determine whether ECM or kinase genes represent therapeutic targets in metastatic RCC.…”

Checkpoint Kinase 2 (CHEK2) Mutation in Renal Cell Carcinoma: A Single-Center Experience

“…Ge et al reported that a rare variant of CHEK2, rs17879961, was associated with decreased risk of renal cell cancer ( 23 ). A study by Ghatalia et al ( 24 ), which compared intra-patient kinase gene expression between RCC and matched normal kidney samples, identified CHEK2 as one of the top 10 overexpressed kinases in metastatic RCC, suggesting a pathological role of activated CHEK2 in RCC. The aim of this retrospective study was to further evaluate the role of I157T and CHEK2*1100delC mutations of CHEK2 gene in ccRCC.…”

Influence of gene expression on survival of clear cell renal cell carcinoma

“…55 A recent study showed that it is overexpressed in metastasis compared to primary RCC tumors. 56 In addition, AURKA is involved in the pathogenesis or progression of hepatocarcinoma, 35 bladder, 36 breast, 37 liver, 38 gastric, 57 colon, 58 non-small cell lung, 59 and pancreatic 60 cancers. AURKB modulates drug response in non-small cell lung, 61 and breast cancers.…”