Overexpression of polo-like kinase 1 is a common and early event in pancreatic cancer

Weichert, Wilko; Schmidt, Mathias; Jacob, Juliane; Gekeler, Volker; Langrehr, Jan M.; Neuhaus, P.; Bahra, Marcus; Denkert, Carsten; Dietel, Manfred; Kristiansen, Glen

doi:10.1159/000085280

Cited by 62 publications

(54 citation statements)

References 25 publications

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“…This has validated Plk1 as an anticancer target (17), but these approaches are difficult to translate to the clinic. The relevance of the Plk1 pathway in pancreatic cancer was highlighted by expression analyses showing that Plk1 was differentially overexpressed in pancreatic cancers as early as pancreatic intraepithelial neoplasia III lesions as opposed to benign acinar pancreatic parenchyma and ductal epithelia, where only focal Plk1 positivity was evidenced (18). A separate analysis found Plk1 mRNA and protein to be overexpressed in clinical pancreatic cancer samples and in cell lines but more importantly decreasing Plk1-induced growth arrest in preclinical models (14).…”

Section: Discussionmentioning

confidence: 99%

A Fine-Needle Aspirate–Based Vulnerability Assay Identifies Polo-Like Kinase 1 as a Mediator of Gemcitabine Resistance in Pancreatic Cancer

Jimeno

Rubio-Viqueira

Rajeshkumar

et al. 2010

Molecular Cancer Therapeutics

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This work aimed to discover targets for combination treatment with gemcitabine in pancreatic cancer. We selected 11 tumors from our live collection of freshly generated pancreatic cancer xenografts with known degrees of varying gemcitabine sensitivity. We briefly (6 h) exposed fine-needle aspiration material to control vehicle or gemcitabine (1 μmol/L) and compared the gene expression of the treated and untreated samples using a reverse transcription-PCR-based, customized low-density array with 45 target genes of therapeutic interest. The gene expression of the untreated sample (which can be considered a baseline/static readout) was not predictive of gemcitabine efficacy in these tumors. Altogether, the only gene that differentiated sensitive versus resistant cases was polo-like kinase 1 (Plk1), showing >50% downregulation in sensitive cases and no change in the resistant cases. Inhibition of Plk1 by either small interfering RNA gene knockdown or with the Plk1 pathway modulator (ON 01910.Na) synergized with gemcitabine in gemcitabine-refractory in vitro models providing mechanistic proof of concept. In vivo experiments in gemcitabine-resistant xenografts showed synergistic activity decreasing cell proliferation and tumor regressions. A quantitative gene expression-based vulnerability assay identified Plk1 as a relevant target dictating the susceptibility of pancreatic cancer to gemcitabine. Dynamic interrogation of cancer has the potential to provide key information about mechanisms of resistance and to enhance individualization of treatment. Mol Cancer Ther; 9(2); 311-8. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

A Fine-Needle Aspirate–Based Vulnerability Assay Identifies Polo-Like Kinase 1 as a Mediator of Gemcitabine Resistance in Pancreatic Cancer

Jimeno

Rubio-Viqueira

Rajeshkumar

et al. 2010

Molecular Cancer Therapeutics

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“…[5] . As a cell cycle control kinase, polo-like kinase1 (PLK1) and its overexpression are highly associated with many human cancers, including bladder [6] , breast [7][8][9][10] , colorectal [11,12] , endometrial [13,14] , esophageal [15][16][17] , gastric [18][19][20][21] , glioma [22] , hepatoblastoma [23] , hepatocellular carcinoma [24] , head and neck [25] , leukemia and lymphoma [26,27] , melanoma [28,29] , nonsmall-cell lung [30] , ovarian [31] , papillary [32] , pancreatic [33,34] , prostate [35] and thyroid cancer [36] . However, up to now, as far as we know, there are few studies available on the overexpression of PLK in HCC.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of polo-like kinase1 predicts a poor prognosis in hepatocellular carcinoma patients

He²,

Lin³

et al. 2009

WJG

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AIM:To elucidate the role of overexpressed polo-like kinase1 (PLK1) in hepatocellular carcinoma (HCC). METHODS:We prospectively collected clinicopathological, immunohistochemical and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) data from 135 HCC patients undergoing successful hepatectomy. The correlations between PLK1 mRNA expression and clinicopathologic variables were analyzed by Mann-Whitney U test. Prognostic factors were identified by univariate and multivariate analyses. RESULTS:Immunohistochemical results showed overexpression of PLK1 was mainly found in tumor tissues compared with tumor-free tissue. A similar mRNA result was obtained by semi-quantitative RT-PCR. A total of 111 samples were positive for PLK1 mRNA expression. The positive expression was correlated with venous invasion, tumor nodules and Edmondson grade. Furthermore, 1, 3, 5-year survival rates in the positive expression group were significantly lower than the negative control group. Multivariate analysis showed that positive PLK1 expression was an independent risk factor for HCC.

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“…[52,53], kde byla prokázána korelace zvyšující se exprese Plk1 s "grade" či "stage" ná-doru. Na druhou stranu spojitost zvý-šené exprese Plk1 a prognózy nebyla prokázána u nádorů prostaty, slinivky a prsu [40,45,47,49].…”

Section: Rodina Proteinů Polo-like Kinázunclassified

“…Stejná je situace u nádorů hlavy a krku [40,41] i jícnu [42]. Zvýšená hladina Plk1 se vyskytuje také u nádorů prsu [43][44][45], jater [46], slinivky [47,48], prostaty [49], stejně tak jako u kolorektálního karcinomu [11,50], nádorů enních, jako např. mozeček, a její exprese je epigeneticky umlčena u glioblastomů [15,16].…”

Section: Plk1 V Nádorové Transformaciunclassified

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

Procházková¹,

Vojtěšek²

2015

Klin Onkol

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Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno SouhrnJednotlivé proteiny z rodiny polo-like kináz (Plk) plní rozdílné, avšak kritické funkce při regulaci buněčného cyklu a koordinují buněčnou odpověď na poškození DNA. Nejvíce prostudovaným z pěti členů této rodiny je protein Plk1. Jedná se o serin/ treonin kinázu, která hraje klíčovou roli v mnoha fázích mitózy, a s její deregulací se setkáváme u různých typů nádorů, kde je její zvýšená hladina většinou asociována s horší prognózou. Z pohledu léčby je také zajímavý vztah Plk1 a proteinu p53. Nejen z těchto důvodů se Plk1 stala jedním z atraktivních cílů pro vývoj protinádorových léčiv. Nejnadějněji se nyní jeví inhibitor ATP-vazebné oblasti Plk1 volasertib (BI 6727), který v doposud provedených klinických studiích prodloužil přežití pa cientů s akutní myeloidní leukemií a nyní je testován v klinické studii fáze III. Ve fázi preklinického testování se nachází také několik inhibitorů polo-box domény (druhého možného místa inhibice polo-like kináz), které by měly zajistit větší specifi tu vůči Plk1. Klíčová slovapolo-like kináza 1 -nádorový supresor p53 -ATP-kompetitivní inhibitory -polo-box doména -klinické studie SummaryIndividual proteins from polo-like kinase (Plk) family fulfi l diff erent but critical functions in regulating cell cycle and coordinate cell response to DNA-damage. The most studied one from this fi ve-member family is Plk1. It is a serine/ threonine kinase that plays a pivotal role in many aspects of mitosis and its deregulation is common in various tumor types where the elevated level is mostly associated with worse prognosis. From the therapeutical point of view, intertwin ed relationship between Plk1 and p53 protein is very interesting and will be discussed. Not only for these reasons, Plk1 has become an attractive target for anti-tumor drug development. The most promising seems to be ATP-binding site inhibitor Volasertib (BI 6727) which provided a survival benefi t for patients with acute myeloid leukemia and is now tested in phase III clinical trial. A new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the polo-box domain, is currently being tested preclinically and are believed to improve Plk1 specifi city.

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Overexpression of polo-like kinase 1 is a common and early event in pancreatic cancer

Cited by 62 publications

References 25 publications

A Fine-Needle Aspirate–Based Vulnerability Assay Identifies Polo-Like Kinase 1 as a Mediator of Gemcitabine Resistance in Pancreatic Cancer

A Fine-Needle Aspirate–Based Vulnerability Assay Identifies Polo-Like Kinase 1 as a Mediator of Gemcitabine Resistance in Pancreatic Cancer

Overexpression of polo-like kinase1 predicts a poor prognosis in hepatocellular carcinoma patients

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

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