High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.
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 outcome...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2015-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4583516?pdf=render |
id |
doaj-808d0e821cff4e1e97f8403c1ebd8bd9 |
---|---|
record_format |
Article |
spelling |
doaj-808d0e821cff4e1e97f8403c1ebd8bd92020-11-25T02:32:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013926710.1371/journal.pone.0139267High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.Joshua C AndersonChristopher D WilleyAmitkumar MehtaKarim WelayaDongquan ChenChristine W DuartePooja GhataliaWaleed ArafatAnkit MadanSunil SudarshanGurudatta NaikWilliam E GrizzleToni K ChoueiriGuru SonpavdeDespite 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.http://europepmc.org/articles/PMC4583516?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joshua C Anderson Christopher D Willey Amitkumar Mehta Karim Welaya Dongquan Chen Christine W Duarte Pooja Ghatalia Waleed Arafat Ankit Madan Sunil Sudarshan Gurudatta Naik William E Grizzle Toni K Choueiri Guru Sonpavde |
spellingShingle |
Joshua C Anderson Christopher D Willey Amitkumar Mehta Karim Welaya Dongquan Chen Christine W Duarte Pooja Ghatalia Waleed Arafat Ankit Madan Sunil Sudarshan Gurudatta Naik William E Grizzle Toni K Choueiri Guru Sonpavde High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes. PLoS ONE |
author_facet |
Joshua C Anderson Christopher D Willey Amitkumar Mehta Karim Welaya Dongquan Chen Christine W Duarte Pooja Ghatalia Waleed Arafat Ankit Madan Sunil Sudarshan Gurudatta Naik William E Grizzle Toni K Choueiri Guru Sonpavde |
author_sort |
Joshua C Anderson |
title |
High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes. |
title_short |
High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes. |
title_full |
High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes. |
title_fullStr |
High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes. |
title_full_unstemmed |
High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes. |
title_sort |
high throughput kinomic profiling of human clear cell renal cell carcinoma identifies kinase activity dependent molecular subtypes. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4583516?pdf=render |
work_keys_str_mv |
AT joshuacanderson highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT christopherdwilley highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT amitkumarmehta highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT karimwelaya highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT dongquanchen highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT christinewduarte highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT poojaghatalia highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT waleedarafat highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT ankitmadan highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT sunilsudarshan highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT gurudattanaik highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT williamegrizzle highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT tonikchoueiri highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes AT gurusonpavde highthroughputkinomicprofilingofhumanclearcellrenalcellcarcinomaidentifieskinaseactivitydependentmolecularsubtypes |
_version_ |
1724820551866777600 |