Systematic analysis of genotype-specific drug responses in cancer

Nayoung Kim, Ningning He, Changsik Kim, Fan Zhang, Yiling Lu, Qinghua Yu, Katherine Stemke-Hale, Joel Greshock, Richard Wooster, Sukjoon Yoon, Gordon B. Mills

    Research output: Contribution to journalArticle

    23 Scopus citations

    Abstract

    A systematic understanding of genotype-specific sensitivity or resistance to anticancer agents is required to provide improved patient therapy. The availability of an expansive panel of annotated cancer cell lines enables comparative surveys of associations between genotypes and compounds of various target classes. Thus, one can better predict the optimal treatment for a specific tumor. Here, we present a statistical framework, cell line enrichment analysis (CLEA), to associate the response of anticancer agents with major cancer genotypes. Multilevel omics data, including transcriptome, proteome and phosphatome data, were integrated with drug data based on the genotypic classification of cancer cell lines. The results reproduced known patterns of compound sensitivity associated with particular genotypes. In addition, this approach reveals multiple unexpected associations between compounds and mutational genotypes. The mutational genotypes led to unique protein activation and gene expression signatures, which provided a mechanistic understanding of their functional effects. Furthermore, CLEA maps revealed interconnections between TP53 mutations and other mutations in the context of drug responses. The TP53 mutational status appears to play a dominant role in determining clustering patterns of gene and protein expression profiles for major cancer genotypes. This study provides a framework for the integrative analysis of mutations, drug responses and omics data in cancers.

    Original languageEnglish (US)
    Pages (from-to)2456-2464
    Number of pages9
    JournalInternational Journal of Cancer
    Volume131
    Issue number10
    DOIs
    StatePublished - Nov 15 2012

      Fingerprint

    Keywords

    • cancer cell line modeling
    • cancer genotype
    • drug sensitivity and resistance
    • network analysis
    • reverse phase protein assay

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Kim, N., He, N., Kim, C., Zhang, F., Lu, Y., Yu, Q., Stemke-Hale, K., Greshock, J., Wooster, R., Yoon, S., & Mills, G. B. (2012). Systematic analysis of genotype-specific drug responses in cancer. International Journal of Cancer, 131(10), 2456-2464. https://doi.org/10.1002/ijc.27529