Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. 7,8,is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G 2 -M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC 50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC 50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700-9. Ó2011 AACR.
Insulin stimulates translocation of glucose transporter isoform type 4 (GLUT4) and the insulin-responsive aminopeptidase (IRAP) from an intracellular storage pool to the plasma membrane in muscle and fat cells. A role for the cytoskeleton in insulin action has been postulated, and the insulin signaling pathway has been well investigated; however, the molecular mechanism by which GLUT4/IRAP-containing vesicles move from an interior location to the cell surface in response to insulin is incompletely understood. Here, we have screened for IRAP-binding proteins using a yeast two-hybrid system and have found that the C-terminal domain of FHOS (formin homolog overexpressed in spleen) interacts with the N-terminal cytoplasmic domain of IRAP. FHOS is a member of the Formin/Diaphanous family of proteins that is expressed most abundantly in skeletal muscle. In addition, there are two novel types of FHOS transcripts generated by alternative mRNA splicing. FHOS78 has a 78-bp insertion and it is expressed mainly in skeletal muscle where it may be the most abundant isoform in humans. The ubiquitously expressed FHOS24 has a 24-bp insertion encoding an in-frame stop codon that results in a truncated polypeptide. It is known that some formin family proteins interact with the actin-binding profilin proteins. Both FHOS and FHOS78 bound to profilin IIa via their formin homology 1 domains, but neither bound profilin I or IIb. Overexpression of FHOS and FHOS78 resulted in enhanced insulin-stimulated glucose uptake in L6 cells to similar levels. However, overexpression of FHOS24, lacking the IRAP-binding domain, did not affect insulin-stimulated glucose uptake. These findings suggest that FHOS mediates an interaction between GLUT4/IRAP-containing vesicles and the cytoskeleton and may participate in exocytosis and/or retention of this membrane compartment.
Background: Polo-like kinase 1 (PLK1) plays an essential role in mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and has been associated with poor prognosis. TAK-960 is a highly selective, orally bioavailable PLK1 inhibitor that inhibits proliferation in multiple cancer cell lines; however, some cancer cell lines are insensitive to TAK-960. To investigate mechanisms of sensitivity to TAK-960 treatment and to identify a potential gene signature that might be useful for clinical development, we examined gene expression, mutation status, and copy number information in cancer cell lines with different TAK-960 sensitivities. Methods: A total of 100 cancer cell lines were treated with 15–5,000 nmol/L of TAK-960 at ONCOTEST GmbH (Freiburg, Germany) using a clonogenic assay. Cell lines with EC50 values <100 nmol/L and >1,000 nmol/L were defined as sensitive and resistant cell lines, respectively. Gene expression data generated using DNA microarray were obtained from ONCOTEST and used to detect sensitive and resistant cell lines which were then analyzed using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood City, CA) and Molecular Concepts Analysis (Rhodes D, et al Neoplasia 2007). In vivo antitumor activity of TAK-960 in 15 mouse xenograft models was evaluated by the treated/control (T/C) tumor volume ratio after once daily oral administration of TAK-960 10 mg/kg for 2 weeks. Mutation status and copy number information of cell lines used to establish the xenograft models were obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Results: Analysis of gene expression data from ONCOTEST cancer cell lines revealed that expression of several genes implicated in the cell-to-cell signaling and interaction, hematological system development and function, hepatic system disease, cell death, tumor morphology, and cellular development network including CDKN2A, CD36, TLR4, TNFRSF11A, IGFBP1, TIMP3 and several chemokine genes were different in sensitive and resistant cell lines. In addition, xenograft tumors (A549, MES-SA/D×5, 786-O, Caki-1, and Ma-1) with a deletion or mutation of CDKN2A, which is a tumor suppressor gene encoding the p16 cell cycle regulatory protein, did not respond to TAK-960 compared with CDKN2A wild-type xenograft tumors (BT474, HT-29, MV4–11, PC-3, H1299, and A2780). Conclusions: These results indicate that CDKN2A status correlated with sensitivity and thus suggest that CDKN2A status may be a useful predictive biomarker of TAK-960 antitumor activity in clinical studies. The role of CDKN2A in modulation of sensitivity to TAK-960 is under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A207.
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