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

TY - JOUR

T1 - Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma

AU - Watt, S A

AU - Pourreyron, C

AU - Purdie, K

AU - Hogan, C

AU - Cole, C L

AU - Foster, N

AU - Pratt, N

AU - Bourdon, J-C

AU - Appleyard, V

AU - Murray, K

AU - Thompson, A M

AU - Mao, X

AU - Mein, C

AU - Bruckner-Tuderman, L

AU - Evans, A

AU - McGrath, J A

AU - Proby, C M

AU - Foerster, J

AU - Leigh, I M

AU - South, A P

PY - 2011/11/17

Y1 - 2011/11/17

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Carcinoma, Squamous Cell

KW - Carrier Proteins

KW - Cell Cycle Proteins

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Keratinocytes

KW - Molecular Targeted Therapy

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins

KW - RNA, Messenger

KW - RNA, Small Interfering

KW - Skin Neoplasms

KW - Tumor Cells, Cultured

U2 - 10.1038/onc.2011.180

DO - 10.1038/onc.2011.180

M3 - Article

C2 - 21602893

SN - 0950-9232

VL - 30

SP - 4666

EP - 4677

JO - Oncogene

JF - Oncogene

IS - 46

M1 - N/A

ER -