Data from Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph⁺ ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph⁺ ALL cell lines in the nanomolar range by the induction of G₀–G₁ arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph⁺ lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph⁺ lymphoid leukemia cells was significantly higher than that in Ph⁻ lymphoid leukemia cells. Of note, three Ph⁺ ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph⁺ ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph⁺ ALL patients after treatment with tyrosine kinase inhibitors. Mol Cancer Ther; 15(1); 94–105. ©2015 AACR.