TY - JOUR T1 - PD-0332991, a Potent and Selective Inhibitor of Cyclin-dependent Kinase 4/6, Demonstrates Inhibition of Proliferation in Renal Cell Carcinoma at Nanomolar Concentrations and Molecular Markers Predict for Sensitivity JF - Anticancer Research JO - Anticancer Res SP - 2997 LP - 3004 VL - 33 IS - 8 AU - JOSHUA E. LOGAN AU - NIKAYEH MOSTOFIZADEH AU - AMRITA J. DESAI AU - ERIKA VON EUW AU - DYLAN CONKLIN AU - VEERAUO KONKANKIT AU - HABIB HAMIDI AU - MARK ECKARDT AU - LEE ANDERSON AU - HSIAO-WANG CHEN AU - CHARLES GINTHER AU - EILEEN TASCHEREAU AU - PETER H. BUI AU - JAMES G. CHRISTENSEN AU - ARIE S. BELLDEGRUN AU - DENNIS J. SLAMON AU - FAIROOZ F. KABBINAVAR Y1 - 2013/08/01 UR - http://ar.iiarjournals.org/content/33/8/2997.abstract N2 - Background: PD-0332991 is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and was evaluated to determine its anti-proliferative effects in 25 renal cell carcinoma (RCC) cell lines. Materials and Methods: Half-maximal inhibitory concentrations (IC50) of PD-0332991 were determined with cell line proliferation assays, as were its effects on the cell cycle, apoptosis, and retinoblastoma (RB) phosphorylation. Molecular markers for response prediction, including p16, p15, cyclin D1 (CCND1), cyclin E1 (CCNE1), E2F transcription factor 1 (E2F1), RB, CDK4 and CDK6, were studied using array comparative genomic hybridization (CGH) and gene expression. Results: IC50 values for PD-0332991 ranged from 25.0 nM to 700 nM, and the agent demonstrated G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation. Through genotype and expression data p16, p15 and E2F1 were identified as having significant association between loss and sensitivity to PD-0332991: p16 (p=0.021), p15 (p=0.047), and E2F1 (p=0.041). Conclusion: PD-0332991 has antiproliferative activity in RCC cell lines, and molecular markers predict for sensitivity to this agent. ER -