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2015 ; 10
(9
): e0139267
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High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma
Identifies Kinase Activity Dependent Molecular Subtypes
#MMPMID26406598
Anderson JC
; Willey CD
; Mehta A
; Welaya K
; Chen D
; Duarte CW
; Ghatalia P
; Arafat W
; Madan A
; Sudarshan S
; Naik G
; Grizzle WE
; Choueiri TK
; Sonpavde G
PLoS One
2015[]; 10
(9
): e0139267
PMID26406598
show ga
Despite the widespread use of kinase-targeted agents in clear cell renal cell
carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling)
of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in
devising a classification system associated with clinical outcomes, and help
identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41
clinically annotated patients who had localized disease at diagnosis were
kinomically profiled using the PamStation®12 high-content phospho-peptide
substrate microarray system (PamGene International). Twelve of these patients
also had matched normal kidneys available that were also profiled. Unsupervised
hierarchical clustering and supervised comparisons based on tumor vs. normal
kidney and clinical outcome (tumor recurrence) were performed and coupled with
advanced network modeling and upstream kinase prediction methods. Unsupervised
clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups
associated with inflammation (A), translation initiation (B), and immune response
and cell adhesions (C) processes. Potential driver kinases implicated include
PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C,
respectively. Of the 9 patients who had tumor recurrence, only one was found in
Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4
substrates in those which progressed compared to others. Twelve tumors with
matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors
compared to adjacent normal renal tissue. As such, comprehensive kinase profiling
of CC-RCC tumors could provide a functional classification strategy for patients
with localized disease and identify potential therapeutic targets.