Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in pancreatic cancer cells but not bone marrow precursor cells

Lin, Yao; Richards, Frances M.; Krippendorff, B-F; Bramhall, Jo L.; Harrington, Jennifer; Bapiro, Tashinga E.; Robertson, Avril A. B.; Zheleva, Daniella; Jodrell, Duncan I.

doi:10.1038/bjc.2012.450

Cited by 34 publications

(30 citation statements)

References 40 publications

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“…In prior preclinical and clinical studies involving AKIs, single agent AKI therapy induced apoptosis in a dose- and time-dependent manner and also potentiated antitumor activity when combined with taxanes by promoting cell death by apoptosis [7, 13–15]. In preclinical studies, MK-5108 robustly potentiated apoptosis when used in combination with docetaxel in HeLaS3 cells and also enhanced the anti-tumor efficacy of docetaxel in both HeLa-luc (human cervical adenocarcinoma) and docetaxel-resistant ES-2 (human ovarian carcinoma) xenograft rat tumors without increasing docetaxel-induced hematopoietic toxicity [9].…”

Section: Discussionmentioning

confidence: 99%

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

et al. 2015

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Summary Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1–2 in 14–21 day cycles either alone (MT; Panel1/n=18; 200 to 1800 mg) or in combination (CT; Panel2/n=17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; 3 patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6–13.5 hours across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

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Section: Discussionmentioning

confidence: 99%

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

et al. 2015

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“…Inhibition of Aurora‐A or its substrates TACC3 and CENP‐A, significantly increases sensitivity to paclitaxel in cancer cells . Consistent with this observation, the Aurora‐A inhibitor CYC3 in combination with paclitaxel can lead to synergistic cytotoxicity in pancreatic cancer cells . In addition, combination of the Aurora‐A inhibitor MLN8237 and docetaxel results in more cell death and a reduction in tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas and mantle cell lymphoma .…”

Section: Targeting Aurora‐a Kinasementioning

confidence: 67%

“…177,178 Consistent with this observation, the Aurora-A inhibitor CYC3 in combination with paclitaxel can lead to synergistic cytotoxicity in pancreatic cancer cells. 179 In addition, combination of the Aurora-A inhibitor MLN8237 and docetaxel results in more cell death and a reduction in tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas and mantle cell lymphoma. 180,181 Mahadevan et al have also reported that MLN8237 combined with docetaxel or vincristine plus rituximab culminates in synergistic curative efficacy in aggressive B-cell non-Hodgkin lymphoma.…”

Section: Akis Combined With Conventional Chemo-and Radiotherapiesmentioning

confidence: 99%

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

Yan

Wang

et al. 2016

Medicinal Research Reviews

208

181

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The Aurora kinase family comprises three serine/threonine kinases, Aurora-A, -B and -C. Among these, Aurora-A and -B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases have been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis.Aurora kinases therefore represent promising targets for anticancer therapeutics. So far, a number of Aurora kinase inhibitors (AKIs) have been generated, of which some are currently undergoing clinical trials. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in contributing tumorigenesis, the recent preclinical and clinical AKI data and potential alternative routes for Aurora-A kinase inhibition.Key words: Aurora-A; Aurora kinase inhibitors (AKIs); targeted cancer therapy; mitosis; tumorigenesis 3 In mammals, the Aurora family of serine/threonine kinases consists of Aurora-A, -B and -C, which share a highly conserved catalytic domain containing auto-phosphorylating sites. The catalytic domain is flanked by a very short C-terminal tail and an N-terminal domain of variable lengths 1,2 . In the C-terminal regions of Auroras, there exists a short amino-acid peptide motif called "destruction box" (D-box). The D-box is recognized by the anaphase-promoting complex/cyclosome (APC/C) for degradation through the ubiquitin/proteasome-dependent pathway ( Fig. 1A). Despite their structural similarities, the expression patterns, cellular localization and physiological functions of these three Aurora kinases are largely distinct.Aurora-A and -B are commonly expressed in most cell types whereas Aurora-C is specially expressed in the testis. Both Aurora-A and -B play key roles in regulating cell-cycle progression from G2 through to cytokinesis. Aurora-C has a unique physiological role in spermatogenesis and functions as a chromosomal passenger protein similar to Aurora-B in mitosis 2 .Overexpression of Aurora-A and -B have been found in multiple types of cancer (Table 1), which function as oncogenes to promote tumorigenesis, providing potential targets for cancer therapy.However, comparatively little information is available regarding the roles of Aurora-C in cancer.In this review, we will focus on recent progress as well as the main unresolved issues associated with Aurora-A in cancer.4 1 FUNCTIONS OF AURORA-A In normal cells a. MitosisIn G1 phase, the level of Aurora-A is rarely detectable. During S phase, a small proportion of Aurora-A is first detected at centrosomes. At late G2 phase, Aurora-A accumulates evidently at centrosomes and becomes activated 3 . During prometaphase and metaphase, active Aurora-A localizes on bipolar spindles and spindle poles after...

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“…The effect of the combination was evaluated using the Bliss Independance model [21], [22] according to the protocol we have described previously [23]. Briefly, an additivity model was built based on single agent data from 5-FU and GEM.…”

Section: Methodsmentioning

confidence: 99%

Anti-Tumour Efficacy of Capecitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer

et al. 2013

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Capecitabine (CAP) is a 5-FU pro-drug approved for the treatment of several cancers and it is used in combination with gemcitabine (GEM) in the treatment of patients with pancreatic adenocarcinoma (PDAC). However, limited pre-clinical data of the effects of CAP in PDAC are available to support the use of the GEMCAP combination in clinic. Therefore, we investigated the pharmacokinetics and the efficacy of CAP as a single agent first and then in combination with GEM to assess the utility of the GEMCAP therapy in clinic. Using a model of spontaneous PDAC occurring in KrasG12D; p53R172H; Pdx1-Cre (KPC) mice and subcutaneous allografts of a KPC PDAC-derived cell line (K8484), we showed that CAP achieved tumour concentrations (∼25 µM) of 5-FU in both models, as a single agent, and induced survival similar to GEM in KPC mice, suggesting similar efficacy. In vitro studies performed in K8484 cells as well as in human pancreatic cell lines showed an additive effect of the GEMCAP combination however, it increased toxicity in vivo and no benefit of a tolerable GEMCAP combination was identified in the allograft model when compared to GEM alone. Our work provides pre-clinical evidence of 5-FU delivery to tumours and anti-tumour efficacy following oral CAP administration that was similar to effects of GEM. Nevertheless, the GEMCAP combination does not improve the therapeutic index compared to GEM alone. These data suggest that CAP could be considered as an alternative to GEM in future, rationally designed, combination treatment strategies for advanced pancreatic cancer.

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Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in pancreatic cancer cells but not bone marrow precursor cells

Cited by 34 publications

References 40 publications

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

Anti-Tumour Efficacy of Capecitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer

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