Specific anti-leukemic activity of PD0332991, a CDK4/6 inhibitor, against Philadelphia-chromosome positive lymphoid leukemia
Menée sur des lignées cellulaires et à l'aide de xénogreffes de leucémies lymphoïdes Ph+, cette étude met en évidence des mécanismes par lesquels un composé appelé PD0332991, un inhibiteur de CDK4/6, exerce une activité antitumorale
S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacological inhibition of altered cell cycle progression would be an effective strategy to control tumors. In the present study, we analyzed the anti-leukemic 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 anti-leukemic 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 post-transcriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, 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 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.
http://mct.aacrjournals.org/content/early/2015/12/04/1535-7163.MCT-14-1065.abstract