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.
authors.affiliation: Department of Melanoma Medical Oncology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0904, Houston, TX 77030, USA.
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.forename: Rosalia
authors.initials: R
authors.lastname: Rabinovsky
authors.forename: Mark
authors.initials: M
authors.lastname: Carey
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.forename: Wanleng
authors.initials: W
authors.lastname: Deng
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cheong
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation* / Q000379:methods*; D006801:Humans; D009154:Mutation; D054547:National Cancer Institute (U.S.); D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D014481:United States
chemical_list: D000970:Antineoplastic Agents