Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set

Eun Sung Park, Rosalia Rabinovsky, Mark Carey, Bryan T. Hennessy, Roshan Agarwal, Wenbin Liu, Zhenlin Ju, Wanleng Deng, Yiling Lu, Hyun Goo Woo, Sang Bae Kim, Jae Ho Cheong, Levi A. Garraway, John N. Weinstein, Gordon Mills, Ju Seog Lee, Michael A. Davies

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer.

Original languageEnglish (US)
Pages (from-to)257-267
Number of pages11
JournalMolecular Cancer Therapeutics
Volume9
Issue number2
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Fingerprint

Proteomics
Protein Array Analysis
Cell Line
Mutation
Pharmaceutical Preparations
Neoplasms
Proteins
Paclitaxel
Critical Pathways
Cell Lineage
Oncogenes
Antineoplastic Agents
Small Interfering RNA
Signal Transduction
Genome
Pharmacology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set. / Park, Eun Sung; Rabinovsky, Rosalia; Carey, Mark; Hennessy, Bryan T.; Agarwal, Roshan; Liu, Wenbin; Ju, Zhenlin; Deng, Wanleng; Lu, Yiling; Woo, Hyun Goo; Kim, Sang Bae; Cheong, Jae Ho; Garraway, Levi A.; Weinstein, John N.; Mills, Gordon; Lee, Ju Seog; Davies, Michael A.

In: Molecular Cancer Therapeutics, Vol. 9, No. 2, 01.01.2010, p. 257-267.

Research output: Contribution to journalArticle

Park, ES, Rabinovsky, R, Carey, M, Hennessy, BT, Agarwal, R, Liu, W, Ju, Z, Deng, W, Lu, Y, Woo, HG, Kim, SB, Cheong, JH, Garraway, LA, Weinstein, JN, Mills, G, Lee, JS & Davies, MA 2010, 'Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set', Molecular Cancer Therapeutics, vol. 9, no. 2, pp. 257-267. https://doi.org/10.1158/1535-7163.MCT-09-0743
Park, Eun Sung ; Rabinovsky, Rosalia ; Carey, Mark ; Hennessy, Bryan T. ; Agarwal, Roshan ; Liu, Wenbin ; Ju, Zhenlin ; Deng, Wanleng ; Lu, Yiling ; Woo, Hyun Goo ; Kim, Sang Bae ; Cheong, Jae Ho ; Garraway, Levi A. ; Weinstein, John N. ; Mills, Gordon ; Lee, Ju Seog ; Davies, Michael A. / Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 2. pp. 257-267.
@article{2419480a42164dceb98abb9b1e4ed129,
title = "Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set",
abstract = "Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer.",
author = "Park, {Eun Sung} and Rosalia Rabinovsky and Mark Carey and Hennessy, {Bryan T.} and Roshan Agarwal and Wenbin Liu and Zhenlin Ju and Wanleng Deng and Yiling Lu and Woo, {Hyun Goo} and Kim, {Sang Bae} and Cheong, {Jae Ho} and Garraway, {Levi A.} and Weinstein, {John N.} and Gordon Mills and Lee, {Ju Seog} and Davies, {Michael A.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1158/1535-7163.MCT-09-0743",
language = "English (US)",
volume = "9",
pages = "257--267",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set

AU - Park, Eun Sung

AU - Rabinovsky, Rosalia

AU - Carey, Mark

AU - Hennessy, Bryan T.

AU - Agarwal, Roshan

AU - Liu, Wenbin

AU - Ju, Zhenlin

AU - Deng, Wanleng

AU - Lu, Yiling

AU - Woo, Hyun Goo

AU - Kim, Sang Bae

AU - Cheong, Jae Ho

AU - Garraway, Levi A.

AU - Weinstein, John N.

AU - Mills, Gordon

AU - Lee, Ju Seog

AU - Davies, Michael A.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer.

AB - Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer.

UR - http://www.scopus.com/inward/record.url?scp=76649106091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76649106091&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-09-0743

DO - 10.1158/1535-7163.MCT-09-0743

M3 - Article

C2 - 20124458

AN - SCOPUS:76649106091

VL - 9

SP - 257

EP - 267

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 2

ER -