Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-10-2019 | Review – Cancer Research

PLK4: a promising target for cancer therapy

Authors: Yi Zhao, Xin Wang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2019

Abstract

Purpose

Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome amplification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer.

Methods

The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic.

Results

PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo.

Conclusions

PLK4 plays an important role in centrosome amplification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.

Anderhub SJ, Kramer A, Maier B (2012) Centrosome amplification in tumorigenesis. Cancer Lett 322:8–17. https://doi.org/10.1016/j.canlet.2012.02.006 CrossRefPubMed

Archambault V, Lepine G, Kachaner D (2015) Understanding the Polo Kinase machine. Oncogene 34:4799–4807. https://doi.org/10.1038/onc.2014.451 CrossRefPubMed

Bao J et al (2018) MiR-126 negatively regulates PLK-4 to impact the development of hepatocellular carcinoma via ATR/CHEK1 pathway. Cell Death Dis 9:1045. https://doi.org/10.1038/s41419-018-1020-0 CrossRefPubMedPubMedCentral

Boveri T (2008) Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci 121(Suppl 1):1–84. https://doi.org/10.1242/jcs.025742 CrossRefPubMed

Chan JY (2011) A clinical overview of centrosome amplification in human cancers. Intern J Biol Sci 7:1122–1144CrossRef

Coelho PA et al (2015) Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse. Open Biol 5:150209. https://doi.org/10.1098/rsob.150209 CrossRefPubMedPubMedCentral

Cunha-Ferreira I et al (2009) The SCF/Slimb ubiquitin ligase limits centrosome amplification through degradation of SAK/PLK4. Curr Biol 19:43–49. https://doi.org/10.1016/j.cub.2008.11.037 CrossRefPubMed

Denu RA, Zasadil LM, Kanugh C, Laffin J, Weaver BA, Burkard ME (2016) Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer. BMC Cancer 16:47. https://doi.org/10.1186/s12885-016-2083-x CrossRefPubMedPubMedCentral

Denu RA, Shabbir M, Nihal M, Singh CK, Longley BJ, Burkard ME, Ahmad N (2018) Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma. Mol Cancer Res 16:517–527. https://doi.org/10.1158/1541-7786.Mcr-17-0197 CrossRefPubMedPubMedCentral

Fischer M, Quaas M, Wintsche A, Muller GA, Engeland K (2014) Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein. Nucleic Acids Res 42:163–180. https://doi.org/10.1093/nar/gkt849 CrossRefPubMed

Fischer M, Quaas M, Steiner L, Engeland K (2016) The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes. Nucleic Acids Res 44:164–174. https://doi.org/10.1093/nar/gkv927 CrossRefPubMed

Fournier M et al (2016) KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification. Nat Commun 7:13227. https://doi.org/10.1038/ncomms13227 CrossRefPubMedPubMedCentral

Gemble S, Basto R (2018) Fast and furious… or not, Plk4 dictates the pace. J Cell Biol 217:1169–1171. https://doi.org/10.1083/jcb.201802084 CrossRefPubMedPubMedCentral

Godinho SA et al (2014) Oncogene-like induction of cellular invasion from centrosome amplification. Nature 510:167–171. https://doi.org/10.1038/nature13277 CrossRefPubMedPubMedCentral

Gonczy P (2015) Centrosomes and cancer: revisiting a long-standing relationship. Nat Rev Cancer 15:639–652. https://doi.org/10.1038/nrc3995 CrossRefPubMed

Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA (2005) The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 7:1140–1146. https://doi.org/10.1038/ncb1320 CrossRefPubMed

Helmke C, Becker S, Strebhardt K (2016) The role of Plk3 in oncogenesis. Oncogene 35:135–147. https://doi.org/10.1038/onc.2015.105 CrossRefPubMed

Holland AJ, Cleveland DW (2014) Polo-like kinase 4 inhibition: a strategy for cancer therapy? Cancer Cell 26:151–153. https://doi.org/10.1016/j.ccr.2014.07.017 CrossRefPubMedPubMedCentral

Holland AJ, Lan W, Niessen S, Hoover H, Cleveland DW (2010) Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability. J Cell Biol 188:191–198. https://doi.org/10.1083/jcb.200911102 CrossRefPubMedPubMedCentral

Holland AJ et al (2012) Polo-like kinase 4 controls centriole duplication but does not directly regulate cytokinesis. Mol Biol Cell 23:1838–1845. https://doi.org/10.1091/mbc.e11-12-1043 CrossRefPubMedPubMedCentral

Hudnall SD, Meng H, Lozovatsky L, Li P, Strout M, Kleinstein SH (2016) Recurrent genetic defects in classical Hodgkin lymphoma cell lines. Leuk Lymphoma 57:2890–2900. https://doi.org/10.1080/10428194.2016.1177179 CrossRefPubMed

Jana SC, Bazan JF, Bettencourt-Dias M (2012) Polo boxes come out of the crypt: a new view of PLK function and evolution. Structure 20:1801–1804. https://doi.org/10.1016/j.str.2012.10.008 CrossRefPubMed

Kawakami M et al (2018a) Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. Proc Natl Acad Sci USA 115:1913–1918. https://doi.org/10.1073/pnas.1719760115 CrossRefPubMed

Kawakami M et al (2018b) Reply to Oegema et al. CFI-400945 and Polo-like kinase 4 inhibition. Proc Natl Acad Sci USA 115:E10810–e10811. https://doi.org/10.1073/pnas.1813967115 CrossRefPubMed

Kazazian K et al (2017) Plk4 promotes cancer invasion and metastasis through Arp2/3 complex regulation of the actin cytoskeleton. Cancer Res 77:434–447. https://doi.org/10.1158/0008-5472.can-16-2060 CrossRefPubMed

Klebba JE, Buster DW, McLamarrah TA, Rusan NM, Rogers GC (2015) Autoinhibition and relief mechanism for Polo-like kinase 4. Proc Natl Acad Sci USA 112:E657–E666. https://doi.org/10.1073/pnas.1417967112 CrossRefPubMed

Kleylein-Sohn J, Westendorf J, Le Clech M, Habedanck R, Stierhof YD, Nigg EA (2007) Plk4-induced centriole biogenesis in human cells. Dev Cell 13:190–202. https://doi.org/10.1016/j.devcel.2007.07.002 CrossRefPubMed

Ko MA, Rosario CO, Hudson JW, Kulkarni S, Pollett A, Dennis JW, Swallow CJ (2005) Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37:883–888. https://doi.org/10.1038/ng1605 CrossRefPubMed

Kulukian A, Holland AJ, Vitre B, Naik S, Cleveland DW, Fuchs E (2015) Epidermal development, growth control, and homeostasis in the face of centrosome amplification. Proc Natl Acad Sci USA 112:E6311–E6320. https://doi.org/10.1073/pnas.1518376112 CrossRefPubMed

Ledoux AC, Sellier H, Gillies K, Iannetti A, James J, Perkins ND (2013) NFkappaB regulates expression of Polo-like kinase 4. Cell Cycle 12:3052–3062. https://doi.org/10.4161/cc.26086 CrossRefPubMedPubMedCentral

Lei Q et al (2018) YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect. Cell Death Dis 9:1066. https://doi.org/10.1038/s41419-018-1071-2 CrossRefPubMedPubMedCentral

Levine MS et al (2017) Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals. Dev Cell 40(313–322):e315. https://doi.org/10.1016/j.devcel.2016.12.022 CrossRef

Li J, Tan M, Li L, Pamarthy D, Lawrence TS, Sun Y (2005) SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia 7:312–323CrossRefPubMedPubMedCentral

Li Z, Dai K, Wang C, Song Y, Gu F, Liu F, Fu L (2016) Expression of polo-like kinase 4(PLK4) in breast cancer and its response to taxane-based neoadjuvant chemotherapy. J Cancer 7:1125–1132. https://doi.org/10.7150/jca.14307 CrossRefPubMedPubMedCentral

Li S, Wang C, Wang W, Liu W, Zhang G (2018) Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia. Medicine (Baltimore) 97:e10734. https://doi.org/10.1097/md.0000000000010734 CrossRef

Liu L, Zhang CZ, Cai M, Fu J, Chen GG, Yun J (2012) Downregulation of polo-like kinase 4 in hepatocellular carcinoma associates with poor prognosis. PLoS One 7:e41293. https://doi.org/10.1371/journal.pone.0041293 CrossRefPubMedPubMedCentral

Lohse I, Mason J, Cao PM, Pintilie M, Bray M, Hedley DW (2017) Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts. Oncotarget 8:3064–3071. https://doi.org/10.18632/oncotarget.13619 CrossRefPubMed

Lopes CAM et al (2018) Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis. J Cell Biol. https://doi.org/10.1083/jcb.201711191 CrossRefPubMedPubMedCentral

Lowery DM, Lim D, Yaffe MB (2005) Structure and function of Polo-like kinases Oncogene 24:248–259. https://doi.org/10.1038/sj.onc.1208280 CrossRefPubMed

Maniswami RR et al (2018) PLK4: a link between centriole biogenesis and cancer. Expert Opin Ther Targets 22:59–73. https://doi.org/10.1080/14728222.2018.1410140 CrossRefPubMed

Marina M, Saavedra HI (2014) Nek2 and Plk4: prognostic markers, drivers of breast tumorigenesis and drug resistance. Front Biosci (Landmark Ed) 19:352–365CrossRef

Mason JM et al (2014) Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell 26:163–176. https://doi.org/10.1016/j.ccr.2014.05.006 CrossRefPubMed

Mittal K, Ogden A, Reid MD, Rida PC, Varambally S, Aneja R (2015) Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma. Cell Cycle 14:2798–2809. https://doi.org/10.1080/15384101.2015.1068478 CrossRefPubMedPubMedCentral

Morris EJ et al (2017) Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1. Nat Commun 8:15289. https://doi.org/10.1038/ncomms15289 CrossRefPubMedPubMedCentral

Nakamura T, Saito H, Takekawa M (2013) SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. Nat Commun 4:1775. https://doi.org/10.1038/ncomms2752 CrossRefPubMed

Pellegrino R et al (2010) Oncogenic and tumor suppressive roles of polo-like kinases in human hepatocellular carcinoma. Hepatology 51:857–868. https://doi.org/10.1002/hep.23467 CrossRefPubMed

Pihan GA, Wallace J, Zhou Y, Doxsey SJ (2003) Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res 63:1398–1404PubMed

Press MF et al (2019) Role for polo-like kinase 4 in mediation of cytokinesis. Proc Natl Acad Sci 116:11309–11318. https://doi.org/10.1073/pnas.1818820116 CrossRefPubMed

Quaas M, Muller GA, Engeland K (2012) p53 can repress transcription of cell cycle genes through a p21(WAF1/CIP1)-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements. Cell Cycle 11:4661–4672. https://doi.org/10.4161/cc.22917 CrossRefPubMedPubMedCentral

Rosario CO et al (2010) Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proc Natl Acad Sci USA 107:6888–6893. https://doi.org/10.1073/pnas.0910941107 CrossRefPubMed

Rosario CO et al (2015) A novel role for Plk4 in regulating cell spreading and motility. Oncogene 34:3441–3451. https://doi.org/10.1038/onc.2014.275 CrossRefPubMed

Rudolph D et al (2009) BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res 15:3094–3102. https://doi.org/10.1158/1078-0432.ccr-08-2445 CrossRefPubMed

Scharow A, Knappe D, Reindl W, Hoffmann R, Berg T (2016) Development of bifunctional inhibitors of polo-like kinase 1 with low-nanomolar activities against the polo-box domain. Chembiochem 17:759–767. https://doi.org/10.1002/cbic.201500535 CrossRefPubMed

Sercin O et al (2016) Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nat Cell Biol 18:100–110. https://doi.org/10.1038/ncb3270 CrossRefPubMed

Shinmura K, Kurabe N, Goto M, Yamada H, Natsume H, Konno H, Sugimura H (2014) PLK4 overexpression and its effect on centrosome regulation and chromosome stability in human gastric cancer. Mol Biol Rep 41:6635–6644. https://doi.org/10.1007/s11033-014-3546-2 CrossRefPubMed

Slevin LK, Nye J, Pinkerton DC, Buster DW, Rogers GC, Slep KC (2012) The structure of the plk4 cryptic polo box reveals two tandem polo boxes required for centriole duplication. Structure 20:1905–1917. https://doi.org/10.1016/j.str.2012.08.025 CrossRefPubMedPubMedCentral

Spaniol K, Boos J, Lanvers-Kaminsky C (2011) An in vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies. Anti-cancer Drugs 22:531–542. https://doi.org/10.1097/cad.0b013e3283454526 CrossRefPubMed

Sredni ST et al (2017a) Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma. Oncotarget 8:111190–111212. https://doi.org/10.18632/oncotarget.22704 CrossRefPubMedPubMedCentral

Sredni ST et al (2017b) A functional screening of the kinome identifies the polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.26551 CrossRefPubMed

Steegmaier M et al (2007) BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 17:316–322. https://doi.org/10.1016/j.cub.2006.12.037 CrossRefPubMed

Suri A et al (2019) Evaluation of protein kinase inhibitors with PLK4 cross-over potential in a pre-clinical model of cancer. Int J Mol Sci. https://doi.org/10.3390/ijms20092112 CrossRefPubMedPubMedCentral

Tian X et al (2018) Polo-like kinase 4 mediates epithelial-mesenchymal transition in neuroblastoma via PI3 K/Akt signaling pathway. Cell Death Dis 9:54. https://doi.org/10.1038/s41419-017-0088-2 CrossRefPubMedPubMedCentral

Tsou MF, Stearns T (2006) Mechanism limiting centrosome duplication to once per cell cycle. Nature 442:947–951. https://doi.org/10.1038/nature04985 CrossRefPubMed

Valsasina B et al (2012) NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther 11:1006–1016. https://doi.org/10.1158/1535-7163.mct-11-0765 CrossRefPubMed

Ward A, Hudson JW (2014) p53-Dependent and cell specific epigenetic regulation of the polo-like kinases under oxidative stress. PLoS One 9:e87918. https://doi.org/10.1371/journal.pone.0087918 CrossRefPubMedPubMedCentral

Ward A, Morettin A, Shum D, Hudson JW (2011) Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice. BMC Cancer 11:71. https://doi.org/10.1186/1471-2407-11-71 CrossRefPubMedPubMedCentral

Ward A, Sivakumar G, Kanjeekal S, Hamm C, Labute BC, Shum D, Hudson JW (2015) The deregulated promoter methylation of the Polo-like kinases as a potential biomarker in hematological malignancies. Leuk Lymphoma 56:2123–2133. https://doi.org/10.3109/10428194.2014.971407 CrossRefPubMed

Wong YL et al (2015) Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science 348:1155–1160. https://doi.org/10.1126/science.aaa5111 CrossRefPubMedPubMedCentral

Wu J, Akhmanova A (2017) Microtubule-Organizing Centers. Annu Rev Cell Dev Biol 33:51–75. https://doi.org/10.1146/annurev-cellbio-100616-060615 CrossRefPubMed

Wu HY, Nazockdast E, Shelley MJ, Needleman DJ (2017) Forces positioning the mitotic spindle: Theories, and now experiments. BioEssays. https://doi.org/10.1002/bies.201600212 CrossRefPubMed

Zhang Z et al (2019) PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma. Cancer Lett 443:91–107. https://doi.org/10.1016/j.canlet.2018.11.034 CrossRefPubMed

Zitouni S, Nabais C, Jana SC, Guerrero A, Bettencourt-Dias M (2014) Polo-like kinases: structural variations lead to multiple functions. Nat Rev Mol Cell Biol 15:433–452. https://doi.org/10.1038/nrm3819 CrossRefPubMed

Zitouni S et al (2016) CDK1 prevents unscheduled PLK4-STIL complex assembly in centriole biogenesis. Curr Biol 26:1127–1137. https://doi.org/10.1016/j.cub.2016.03.055 CrossRefPubMedPubMedCentral

Title: PLK4: a promising target for cancer therapy
Authors: Yi Zhao
Xin Wang
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 10/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-02994-0

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2019

Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers

Predictive factors for survival outcomes of oligometastatic prostate cancer patients treated with metastases-directed therapy: a recursive partitioning-based analysis

A novel panel of stool-based DNA biomarkers for early screening of colorectal neoplasms in a Chinese population

The role of autologous stem cell transplantation in peripheral T cell lymphoma: a long-term follow-up single-center experience

Validity of using immunohistochemistry to predict treatment outcome in patients with non-small cell lung cancer not otherwise specified

Metastatic lymph node burden predictive of survival in patients undergoing primary surgery for laryngeal and hypopharyngeal cancer

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage