Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma

Stephen Watt, C. Pourreyron, K. Purdie, C. Hogan, C. L. Cole, N. Foster, N. Pratt, Jean-Christophe Bourdon, V. Appleyard, K. Murray, Alastair Thompson, X. Mao, C. Mein, L. Bruckner-Tuderman, A. Evans, J. A. McGrath, C. M. Proby, J. Foerster, Irene Leigh, Andrew South (Lead / Corresponding author)

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    47 Citations (Scopus)

    Abstract

    Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture. Candidate drivers of cSCC development were derived by first defining a set of in vitro cancer genes and then comparing their expression in a range of clinical data sets containing normal skin, cSCC and the benign hyper-proliferative condition psoriasis. A small interfering RNA (siRNA) screen of the resulting 21 upregulated genes has yielded targets capable of reducing xenograft tumor volume in vivo. Small-molecule inhibitors for one target, Polo-like kinase-1 (PLK1), are already in clinical trials for other malignancies, and our data show efficacy in cSCC. Another target, C20orf20, is identified as being overexpressed in cSCC, and siRNA-mediated knockdown induces apoptosis in vitro and reduces tumor growth in vivo. Thus, our approach has shown established and uncharacterized drivers of tumorigenesis with potent efficacy as therapeutic targets for the treatment of cSCC. © 2011 Macmillan Publishers Limited All rights reserved.
    Original languageEnglish
    Pages (from-to)4666-4677
    Number of pages12
    JournalOncogene
    Volume30
    Issue number46
    DOIs
    Publication statusPublished - Nov 2011

    Keywords

    • cutaneous squamous cell carcinoma
    • primary cell culture
    • gene expression analysis
    • therapeutic targets
    • PLK1
    • POLO-LIKE KINASE
    • GENE-EXPRESSION PATTERNS
    • CHRONIC MYELOID-LEUKEMIA
    • NONMELANOMA SKIN-CANCER
    • EPITHELIAL-CELLS
    • ANALYSIS DEFINES
    • BREAST-CANCER
    • IN-VIVO
    • LINES
    • IDENTIFICATION

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