Preclinical Evaluation of AMG 900, a Novel Potent and Highly Selective Pan-Aurora Kinase Inhibitor with Activity in Taxane-Resistant Tumor Cell Lines

Soft tissue sarcoma (STS) are rare and aggressive tumours. Their classification includes numerous histological subtypes of frequent poor prognosis. Liposarcomas (LPS) are the most frequent type among them, and the aggressiveness and deep localization of dedifferentiated LPS are linked to high levels of recurrence. Current treatments available today lead to five-year overall survival has remained stuck around 60–70% for the past three decades. Here, we highlight a correlation between Aurora kinasa A (AURKA) and AURKB mRNA overexpression and a low metastasis-free survival. AURKA and AURKB expression analysis at genomic and protein level on a 9-STS cell lines panel highlighted STS heterogeneity, especially in LPS subtype. AURKA and AURKB inhibition by RNAi and drug targeting with AMG 900, a pan Aurora Kinase inhibitor, in four LPS cell lines reduces cell survival and clonogenic proliferation, inducing apoptosis and polyploidy. When combined with doxorubicin, the standard treatment in STS, aurora kinases inhibitor can be considered as an enhancer of standard treatment or as an independent drug. Kinome analysis suggested its effect was linked to the inhibition of the MAP-kinase pathway, with differential drug resistance profiles depending on molecular characteristics of the tumor. Aurora Kinase inhibition by AMG 900 could be a promising therapy in STS.

Download Full-text

Cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cell lines characterized for EGFR expression and K-ras mutation

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14583 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14583-e14583 ◽

Cited By ~ 1

Author(s):

J. Barriere ◽

J. Fischel ◽

P. Formento ◽

N. Renée ◽

M. Francoual ◽

...

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Mononuclear Cells ◽

Kinase Inhibitor ◽

Ex Vivo ◽

Human Cancer ◽

Tumor Cell Lines ◽

Ras Mutation ◽

Egfr Expression ◽

Mutational Status

e14583 Background: Mutated K-ras protein is a strong predictive factor of cetuximab resistance, bypassing the classical direct inhibitory effect on epidermal growth factor receptor (EGFR) signaling. However, cetuximab is also able to mediate ADCC, which may be part of the clinical response. The aim of this ex-vivo study was to quantify cetuximab-mediated ADCC on various human cancer cell lines characterized for EGFR-expression and K-ras mutation. Methods: Two K-ras mutated cell lines over-expressing EGFR and resistant to anti-EGFR tyrosine kinase inhibitor were tested (Capan-1 and Capan-2, pancreatic), along with 2 K-ras wild-type cell lines over- expressing EGFR (CAL166, head and neck; A431, epidermoid carcinoma) and an EGFR-negative cell line (OCM1, uveal melanoma). The tested monoclonal antibodies (mAbs) were: cetuximab (Merck, anti-EGFR IgG1 mAb), panitumumab (Amgen, anti-EGFR IgG2 mAb), and as a negative control, rituximab (Roche, IgG1 anti-CD20 mAb). ADCC (51Cr release assay) was performed using freshly- isolated peripheral blood mononuclear cells from a healthy donor. Results were expressed as % of potentially maximum 51Cr release. Results: Cetuximab mediates ADCC against EGFR-over-expressing cell lines CAL166 (38.4 ± 3.1 %), A431 (13.5 ± 1.7 %), Capan-1 (31.2 ± 0.8 %) and Capan-2 (27.8 ± 8.6 %) irrespective of the K-ras mutational status, but not against EGFR-negative OCM-1 (6.2 ± 1 %). Conversely, unlike IgG1 cetuximab, the anti-EGFR IgG2 panitumumab and the irrelevant antibody rituximab were both unable to induce significant ADCC (< 10 % on all tested cell lines). Conclusions: Cetuximab-mediated ADCC is independent of the K-ras mutational status of the tumor cell lines. Present data suggest that cetuximab may remain of clinical interest in K-ras-mutated patients. Immunostimulation, as well as new generation anti-EGFR mAbs with improved ability to induce ADCC, may be promising in the management of K-ras-mutated patients. No significant financial relationships to disclose.

Download Full-text

275 The effect of Aurora kinase inhibitor, ZM447439, on human mammary eptihelial cell lines with BRCA2 mutation

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(10)71080-6 ◽

2010 ◽

Vol 8 (5) ◽

pp. 72

Author(s):

L. Vidarsdottir ◽

A.M. Halldorsdottir ◽

G. Steingrimsdottir ◽

S.K. Bodvarsdottir ◽

H.M. Ogmundsdottir ◽

...

Keyword(s):

Cell Lines ◽

Kinase Inhibitor ◽

Brca2 Mutation ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor

Download Full-text

Effect of CCT137690 on long non-coding RNA expression profiles in MCF-7 and MDA-MB-231 cell lines

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2019.4155 ◽

2019 ◽

Author(s):

Tuğçe Balcı Okcanoğlu ◽

Çağla Kayabaşı ◽

Cumhur Gündüz

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Kinase Inhibitor ◽

Expression Profiles ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor ◽

Er Positive ◽

Mcf 7

Long non-coding RNAs (lncRNAs) are involved in a range of biological processes, such as cellular differentiation, migration, apoptosis, invasion, proliferation, and transcriptional regulation. The aberrant expression of lncRNAs plays a significant role in several cancer types. Aurora kinases are increasingly expressed in various malignancies; accordingly, the inhibition of these enzymes may represent a novel approach for the treatment of various cancers. CCT137690, an Aurora kinase inhibitor, displays an anti-proliferative activity in human cancer cell lines. The aim of the present study was to investigate the anti-proliferative and cytotoxic effects of CCT137690 on estrogen receptor (ER)-positive human breast cancer cell line (MCF-7) and ER-negative human breast cancer cell line (MDA-MB-231). In addition, this study was targeted toward determining the changes induced in lncRNA expression levels following the initiation of Aurora kinase inhibitor treatment. The cytotoxic effects of CCT137690 were determined by means of the xCELLigence system. Furthermore, the anti-proliferative role of CCT137690 in breast cancer was investigated by checking the changes in lncRNA expression profiles using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The half-maximal inhibitory concentrations (IC50) of CCT137690 were determined as 4.5 μM (MCF-7) and 7.27 μM (MDA-MB-231). Several oncogenic lncRNAs (e.g., PRINS, HOXA1AS, and NCRMS) were downregulated in both ER-negative and ER-positive cell lines. On the other hand, tumor suppressor lncRNAs (e.g., DGCR5 and IGF2AS) were upregulated in the ER-positive cell line. After CCT137690 treatment, HOXA11AS and PCAT-14 lncRNAs were downregulated in the ER-positive cell lines. In addition, MER11C, SCA8, BC200, HOTAIR, PCAT-1, UCA1, SOX2OT, and HULC lncRNAs were downregulated in the ER-negative cell lines. The results of the present study indicated that Aurora kinase inhibitor CCT137690 could be a potential anti-cancer agent for breast cancer treatment.

Download Full-text

AP23846, a novel and Highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes

Yearbook of Oncology ◽

10.1016/s1040-1741(08)70509-8 ◽

2007 ◽

Vol 2007 ◽

pp. 345-346

Author(s):

M.S. Gordon

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Tumor Cell ◽

Cell Lines ◽

Solid Tumor ◽

Kinase Inhibitor ◽

Vascular Endothelial ◽

Tumor Cell Lines ◽

Human Solid Tumor ◽

Endothelial Growth Factor

Download Full-text

An Automated Image Capture and Quantitation Approach to Identify Proteins Affecting Tumor Cell Proliferation

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057103262842 ◽

2004 ◽

Vol 9 (3) ◽

pp. 216-222 ◽

Cited By ~ 11

Author(s):

Kaumudi M. Bhawe ◽

Robert A. Blake ◽

Douglas O. Clary ◽

Peter M. Flanagan

Keyword(s):

Cell Proliferation ◽

Tumor Cell ◽

Cell Lines ◽

Kinase Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Functional Assay ◽

Tumor Cell Lines ◽

Tumor Cell Proliferation ◽

Adenoviral Infection

To facilitate the characterization of proteins that negatively regulate tumor cell proliferation in vitro, the authors have implemented a high-throughput functional assay that measures S-phase progression of tumor cell lines. For 2 tumor cell lines—human melanoma A375 and human lung carcinoma A549—conditions were established using the cyclin-dependent kinase inhibitor, p27kip; the tumor suppressor p53, a kinase-inactive allele of the cell cycle-regulated serine/threonine kinase Aurora2; and the G1/S drug block, aphidicolin. For screening purposes, gene libraries were delivered by adenoviral infection. Cells were fixed and labeled by immunocytochemistry, and an automated image acquisition and analysis package on a Cellomics ArrayScan®II was used to quantify the effects of these treatments on cell proliferation. The assay can be used to identify novel proteins involved in proliferation and serves as a more robust, reproducible, and sensitive alternative to enzyme-linked immunosorbent assay (ELISA)-based technologies.

Download Full-text