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

• Published in: Molecular cancer therapeutics Vol. 15; no. 1; pp. 94 - 105
• Main Authors: Nemoto, Atsushi, Saida, Satoshi, Kato, Itaru, Kikuchi, Jiro, Furukawa, Yusuke, Maeda, Yasuhiro, Akahane, Koshi, Honna-Oshiro, Hiroko, Goi, Kumiko, Kagami, Keiko, Kimura, Shinya, Sato, Yuko, Okabe, Seiichi, Niwa, Akira, Watanabe, Kenichiro, Nakahata, Tatsutoshi, Heike, Toshio, Sugita, Kanji, Inukai, Takeshi
• Format: Journal Article
• Language: English
• Published: United States 01.01.2016
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin D2 - genetics; Cyclin D2 - metabolism; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Fusion Proteins, bcr-abl - genetics; Humans; Mice; Mutation; Piperazines - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-14-1065

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.