Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models

Alessandro Natoni(Ollscoil na Gaillimhe – University of Galway), Mark Coyne(Ollscoil na Gaillimhe – University of Galway), Alan J. Jacobsen(Ollscoil na Gaillimhe – University of Galway), Michael D. Rainey(Ollscoil na Gaillimhe – University of Galway), Gemma O'Brien(Ollscoil na Gaillimhe – University of Galway), Sandra Healy(Ollscoil na Gaillimhe – University of Galway), Alessia Montagnoli(Nerviano Medical Sciences), Jürgen Moll(Nerviano Medical Sciences), Michael O’Dwyer(Ollscoil na Gaillimhe – University of Galway), Corrado Santocanale(Ollscoil na Gaillimhe – University of Galway)
Cancers
July 24, 2013
10.3390/cancers5030901
Cited by 22Open Access
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Abstract

Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma.

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