Effect of PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, on proliferation in renal cell carcinoma at nanomolar concentrations and prediction of sensitivity by molecular markers.

413 Background: Cell cycle dysregulation is prevalent in renal cell carcinoma (RCC). PD-0332991 is an orally active, potent, and selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, blocking retinoblastoma (Rb) phosphorylation at nanomolar concentrations. Methods: 28 RCC and immortalized kidney cell lines were used to examine the effects of PD-0332991 on proliferation to determine the half maximal inhibitory concentration (IC50). Effects of PD-0332991 on cell-cycle, apoptosis, and Rb phosphorylation were assessed with flow cytometry and western blot analysis for five of the cell lines: RCC-HB and SW 156 (sensitive/malignant), R444 and Hs 891.T (resistant/malignant), and CCD 1103 (resistant/immortalized non-malignant). Molecular markers for response prediction were studied using array CGH and gene expression profiling. Results: Concentration-dependent inhibition of proliferation was identified in response to PD-0332991, with IC50values ranging from 25.0nM up to 700nM; five cell lines were identif...