Abstract A207: Discovery of molecular mechanisms underlying cellular sensitivity to the PLK1 inhibitor TAK-960.

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 EC 50 values 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.