Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

Raab, Monika; Kappel, Sven; Krämer, Andrea; Sanhaji, Mourad; Matthess, Yves; Kurunci‐Csacsko, Elisabeth; Calzada‐Wack, Julia; Rathkolb, Birgit; Rozman, Jan; Adler, Thure; Busch, Dirk H.; Espósito, Irene; Fuchs, Helmut; Gailus‐Durner, Valérie; Klingenspor, Martin; Wolf, Eckhard; Sänger, Nicole; Prinz, Florian; Angelis, Martin Hrabé de; Seibler, Jost; Yuan, Juping; Bergmann, Martin; Knecht, Rainald; Kreft, Bertolt; Strebhardt, Klaus

doi:10.1038/ncomms1395

Cited by 79 publications

(95 citation statements)

References 52 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…BI2536 was also shown to have anticancer effects in a panel of over 30 different types of cancer cell lines [29][30][31]. Clinical trials of drugs targeting PLK1 have reported only moderate side effects [29,30]. Thus, our preliminary results and published reports indicate that PLK1 is a viable target to treat refractory MCL.…”

Section: Introductionmentioning

confidence: 48%

“…BI2536 is a small molecule inhibitor of PLK1 and was chosen for use in our studies because it displays remarkably potent and selective inhibition of PLK1. BI2536 was also shown to have anticancer effects in a panel of over 30 different types of cancer cell lines [29][30][31]. Clinical trials of drugs targeting PLK1 have reported only moderate side effects [29,30].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

et al. 2013

View full text Add to dashboard Cite

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) which is one of the most aggressive lymphomas. Despite recent improvements in therapies, the development of therapy-resistance is still a major problem; therefore, in order to understand the molecular basis of therapy-resistance, stable therapy-resistant MCL cell lines have been established by us. Based on the gene expression profiles of these cell lines, Polo-like kinase 1 (PLK1) was chosen as a therapeutic target. In this paper, we demonstrate a significant antilymphoma effect of targeting PLK1 in therapy-resistant MCL cells and primary MCL cells from refractory patients. PLK1 knockdown with the antisense oligonucleotide (ASO)/or small molecule inhibitor BI2536 showed significantly decreased proliferation and increased apoptosis in therapy-resistant MCL cell lines and MCL primary cells. Additionally, the direct proteinprotein interaction partners of PLK1 were mapped using ingenuity pathway and confirmed the level of association of these partners with PLK1 based on their expression changes following PLK1 knockdown using real-time PCR. Results suggest that PLK1 is a viable target for the treatment of therapy-resistant MCL.

show abstract

Section: Introductionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

et al. 2013

View full text Add to dashboard Cite

show abstract

“…PLK1 depletion/inhibition triggers apoptosis in various cancer cell lines, and impairs tumor growth in mice (17). PLK1 depletion/inhibition preferentially kills cancer cells compared with normal cells (18)(19)(20) and p53-defective cancer cells compared with p53 wild-type cancer cells (21)(22)(23). Several PLK1 inhibitors have been developed; some of them, such as BI-2536, have been evaluated in clinical trials (8,(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

et al. 2013

View full text Add to dashboard Cite

Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G 2 -M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin þ cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. Cancer Res; 73(2); 813-23. Ó2012 AACR.

show abstract

“…The expression of PLK1 seems important for cell survival and growth, as our study shows that PLK1 knockdown reduced proliferation and induced apoptosis in ALL cell lines, an effect that was also observed in solid tumor and AML cell lines. [21][22][23][35][36][37][38][39][40] The TCF3-translocated 697 cell line did not display the strongest phenotypic effect upon PLK1 knockdown, despite having the highest PLK1 expression. However, PLK1 expression was relatively high in all cell lines (data not shown), probably due to their proliferative capacity, and factors like transfection efficiency and rate of protein knockdown differ between PLK1 in childhood acute lymphoblastic leukemia haematologica | 2013; 98 (10) 1543 We have previously shown that AURKB protein expression is up-regulated in pediatric ALL and correlates with sensitivity to an AURKB inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…PLK1 silencing also markedly inhibited growth of several types of cancer cells, especially p53-deficient types, while barely affecting the growth of normal cells like human umbilical vein endothelial cells, fibroblasts and keratinocytes. 35,43,45 In addition, PLK1-depleted mouse models showed that even very low remaining levels of PLK1 were sufficient to sustain normal hematopoiesis, spermatogenesis and normal cell proliferation. 35 These are all indications that cancer cells may be more dependent on PLK1 expression and more sensitive to PLK1 inhibition than normal cells, offering a therapeutic window for PLK1-targeting drugs.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

et al. 2013

View full text Add to dashboard Cite

This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. ABSTRACTinhibitor highly selective for PLK1 and the first orally administered selective PLK1 inhibitor entering phase I clinical trials 25 (clinicaltrials.gov identifier: NCT01014429). This study shows the potential of PLK1-targeting therapeutics in the treatment of childhood ALL, and indicates their value for further clinical evaluation. Methods Cell linesCell lines (DSMZ, Braunschweig, Germany) were cultured in RPMI+Glutamax with pen-strep, fungizone (Life Technologies, Bleiswijk, The Netherlands) and 10% or 20% fetal calf serum (Integro, Zaandam, The Netherlands), at 37ºC and 5% CO 2 .

show abstract

Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

Cited by 79 publications

References 52 publications

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

Contact Info

Product

Resources

About