The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

Pajtler, Kristian W.; Sadowski, Natalie; Ackermann, Sandra; Althoff, Kristina; Schönbeck, K; Batzke, Katharina; Schäfers, Simon; Odersky, Andrea; Heukamp, Lukas C.; Astrahantseff, Kathy; Künkele, Annette; Deubzer, Hedwig E.; Schramm, Alexander; Sprüssel, Annika; Thor, Theresa; Lindner, Sven; Eggert, Angelika; Fischer, Matthias; Schulte, Johannes H.

doi:10.18632/oncotarget.14268

Cited by 38 publications

(25 citation statements)

References 64 publications

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“…Another major field in PLK1 research is developing PLK1 small‐molecule inhibitors as drug therapies in diseases such as cancer (reviewed in Elizabeth, Gutteridge, Ndiaye, Liu, & Ahmad, ; Murugan et al, ). Numerous studies have tested PLK1 inhibitors, including BI2536, as potential cancer therapeutics for advanced metastatic tumors, including prostate cancer (Hou et al, ; Zhang et al, ), lung cancer (Awad et al, ; Breitenbuecher et al, ), neuroblastoma (Pajtler et al, ), and non‐Hodgkin's lymphoma (Vose et al, ) to name a few. These studies suggest elevated levels of PLK1 expression in highly metastatic and advanced cancers, leads to chromosome instability and aneuploidy (Yamamoto et al, ), providing these cells an advantage to overgrow and invade tissues.…”

Section: Plk1‐scaffold Interactionsmentioning

confidence: 99%

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

Colicino

Hehnly

2018

Cytoskeleton

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During cell division, duplicated genetic material is separated into two distinct daughter cells. This process is essential for initial tissue formation during development and to maintain tissue integrity throughout an organism's lifetime. To ensure the efficacy and efficiency of this process, the cell employs a variety of regulatory and signaling proteins that function as mitotic regulators and checkpoint proteins. One vital mitotic regulator is polo‐like kinase 1 (PLK1), a highly conserved member of the polo‐like kinase family. Unique from its paralogues, it functions specifically during mitosis as a regulator of cell division. PLK1 is spatially and temporally enriched at three distinct subcellular locales; the mitotic centrosomes, kinetochores, and the cytokinetic midbody. These localization patterns allow PLK1 to phosphorylate specific downstream targets to regulate mitosis. In this review, we will explore how polo‐like kinases were originally discovered and diverged into the five paralogues (PLK1‐5) in mammals. We will then focus specifically on the most conserved, PLK1, where we will discuss what is known about how its activity is modulated, its role during the cell cycle, and new, innovative tools that have been developed to examine its function and interactions in cells.

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Section: Plk1‐scaffold Interactionsmentioning

confidence: 99%

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

Colicino

Hehnly

2018

Cytoskeleton

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“…Small molecule kinase inhibitor screening by Grinshtein et al [177] identified Polo-like kinase 1 (PLK-1) as the potential target for NB tumor initiating cells. To that end, a study by Pajtler et al [178] demonstrated that imidazotriazine (GSK461364), a competitive inhibitor for ATP binding to PLK1 which is in clinical development promoted cell death, inhibited clonal expansion and exerted anti-tumoral activity in vivo.…”

Section: Csc-targeted Therapymentioning

confidence: 99%

“…Pajtler et al [178] Berberine Vimentin, fibronectin, E-cadherin, laminin, Smad, PI3/Akt, Ras-Raf-ERK Naveen et al [179] XAV939 a small molecule tankyrase (TNKS) inhibitor…”

Section: Drug Targetsmentioning

confidence: 99%

Cancer stem cells in neuroblastoma therapy resistance

Aravindan¹,

Jain²,

Somasundaram³

et al. 2019

CDR

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Neuroblastoma (NB) is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths. This mortality rate has been attributed to the > 50% frequency of relapse despite intensive, multimodal clinical therapy in patients with progressive NB. Given the disease's heterogeneity and developed resistance, attaining a cure after relapse of progressive NB is highly challenging. A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells (CSCs). In this review, we present the current understanding of NB-CSCs, their intrinsic role in tumorigenesis, their function in disease progression, and their influence on acquired therapy resistance and tumor evolution. In particular, this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB, the function of pre-existing CSCs in NB progression and therapy response, the formation and influence of induced CSCs (iCSCs) in drug resistance and tumor evolution, and the development of a CSC-targeted therapeutic approach.

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“…PLK1'in inhibisyonu, hücre döngüsünün dur-durulmasına neden olmakta ve apoptozu indüklemektedir. 71,72 Pek çok kanserden farklı olarak, TP53 mutasyonları nöroblastomda daha az görülmektedir. TP53 aracılı hücre ölüm yolağı-nın negatif bir düzenleyicisi olan PPM1D'nin inhibisyonu, CHK2/ TP53 aracılığıyla apoptozu indüklemek için yeni bir yaklaşım olarak öneril-miştir.…”

Section: Hedefe Yöneli̇k Tedavi̇ Yaklaşimi Ve Gelecek Perspekti̇flerunclassified

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

Bağca¹,

Avcı²

2017

Turkiye Klinikleri J Neur

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Ö ÖZ ZE ET T Nöroblastom, embriyonik dönemde ortaya çıkan, nöral krest kaynaklı nadir bir kanser tü-rüdür. Santral sinir sistemindeki herhangi bir bölgeden ama sıklıkla böbrek üstü bezlerinden köken almaktadır. Hastalarda genellikle lenf düğümlerine, kemik iliğine ve kemiğe metastaz gerçekleş-mesi sağkalımı olumsuz şekilde etkilemektedir. Nöroblastomun başlangıçta tamamen ailesel bir hastalık olduğu düşünülse de ailesel olanlar tüm hastaların küçük bir bölümünü oluşturmaktadır. Nöroblastom patogenezinde rol aldığı tanımlanmış olan belli başlı mutasyonlar MYCN, ALK, PHOX2B, ATRX ve TERT genlerini içermektedir. Bununla birlikte artık sadece genetik değil epigenetik düzenlenim hatalarının da diğer pek çok hastalıkta olduğu gibi, nöroblastom patogenezinde görev aldığı bilinmektedir. Kromatin yapının regülasyonunu sağlayan histon modifikasyonları, gen ifadesinin kontrolünde görev alan DNA metilasyonu ve ncRNA'lar aracılığıyla gerçekleşen bu düzenlemelerin nöroblastomla ilişkisi araştırılmaktadır. Konvansiyonel tedavi, hastaların prognostik özelliklerine bağlı olarak cerrahi müdahale ile tümörün çıkarılması, kemoterapi, otolog kök hücre nakli ve radyoterapi yaklaşımlarını içermesine rağmen, kemoterapötiklere karşı direnç gelişimi ya da duyarsızlık sorunları sıklıkla ortaya çıkmaktadır. Bu sorunların üste-sinden gelmek, sağkalımı ve yaşam kalitesini artırmak için güncel tedavi yaklaşımları, doğrudan kanser hücresini elimine etmeyi amaçlayan "hedefe yönelik tedavi" yaklaşımlarının geliştirilme-sine odaklanmış durumdadır. Bu çalışmada, nöroblastom genetiği ve epigenetiği hakkında bildiklerimizin ve hedefe yönelik tedavi yaklaşımlarında nerede olduğumuzun güncel literatür verileri ile ortaya konulması amaçlanmıştır.A An na ah h t ta ar r K Ke e l li i m me e l le er r: : Nöroblastom; genetik; neoplastik kök hücreler; moleküler hedefe yönelik tedavi A AB BS S T TR RA AC CT T Neuroblastoma is a rare cancer arising in the embryonic stage, originating from the neural crest. It originates from any region of the central nervous system, but often emerges from the adrenal glands. In most cases, metastasis to lymph nodes, bone marrow, and bone affect survival rates adversely. Although neuroblastoma is considered as a completely familial disease at the beginning, familial cases constitute a small part of all cases. The major mutations identified in the pathogenesis of neuroblastoma include MYCN, ALK, PHOX2B, ATRX and TERT genes. Nevertheless, it is now known that not only genetic but also epigenetic aberrations of gene expression are involved in the pathogenesis of neuroblastoma as well as many other diseases. Epigenetic regulations which include histone modifications that regulate the chromatin structure; DNA methylation which is involved in the control of gene expression; and ncRNAs, is being searched in relation to neuroblastoma. Conventional treatment includes surgical removal of tumors, chemotherapy, autologous stem cell transplantation, radiotherapy approaches according to the prognostic features of the patients, however, res...

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The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

Cited by 38 publications

References 64 publications

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

Cancer stem cells in neuroblastoma therapy resistance

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

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