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Frequent Alterations in the Expression of Serine/Threonine Kinases in Human Cancers

¹ Istituto FIRC di Oncologia Molecolare; ² Istituto Europeo di Oncologia; ³ Ospedale Luigi Sacco; ⁴ Fondazione Policlinico, Mangiagalli e Regina Elena; ⁵ University of Milan, Milan, Italy; ⁶ Azienda Sanitaria Ospedale Maggiore della Carita, Novara, Italy; and ⁷ Sugen/Pharmacia, South San Francisco, California

Requests for reprints: Pier Paolo Di Fiore, Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy. Phone: 39-2-574303247; Fax: 39-2-574303231; E-mail: pierpaolo.difiore{at}ifom-ieo-campus.it.

Protein kinases constitute a large family of regulatory enzymes involved in the homeostasis of virtually every cellular process. Subversion of protein kinases has been frequently implicated in malignant transformation. Within the family, serine/threonine kinases (STK) have received comparatively lesser attention, vis-a-vis tyrosine kinases, in terms of their involvement in human cancers. Here, we report a large-scale screening of 125 STK, selected to represent all major subgroups within the subfamily, on nine different types of tumors (200 patients), by using in situ hybridization on tissue microarrays. Twenty-one STK displayed altered levels of transcripts in tumors, frequently with a clear tumor type-specific dimension. We identified three patterns of alterations in tumors: (a) overexpression in the absence of expression in the normal tissues (10 kinases), (b) overexpression in the presence of expression by normal tissues (8 kinases), and (c) underexpression (3 kinases). Selected members of the three classes were subjected to in-depth analysis on larger case collections and showed significant correlations between their altered expression and biological and/or clinical variables. Our findings suggest that alteration in the expression of STK is a relatively frequent occurrence in human tumors. Among the overexpressed kinases, 10 were undetectable in normal controls and are therefore ideal candidates for further validation as potential targets of molecular cancer therapy. (Cancer Res 2006; 66(16): 8147-54)

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