{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:21:13Z","timestamp":1787235673798,"version":"build-2736575974"},"reference-count":84,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T00:00:00Z","timestamp":1589846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Roche S.p.A","award":["Prot. N. 0001663 CNR"],"award-info":[{"award-number":["Prot. N. 0001663 CNR"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugated to the microtubule-targeting agent emtansine (DM1). T-DM1 is an effective agent in the treatment of patients with HER2-positive breast cancer whose disease has progressed on the first-line trastuzumab containing chemotherapy. However, both primary and acquired tumour resistance limit its efficacy. Increased levels of the phosphorylated form of Translationally Controlled Tumour Protein (phospho-TCTP) have been shown to be associated with a poor clinical response to trastuzumab therapy in HER2-positive breast cancer. Here we show that phospho-TCTP is essential for correct mitosis in human mammary epithelial cells. Reduction of phospho-TCTP levels by dihydroartemisinin (DHA) causes mitotic aberration and increases microtubule density in the trastuzumab-resistant breast cancer cells HCC1954 and HCC1569. Combinatorial studies show that T-DM1 when combined with DHA is more effective in killing breast cells compared to the effect induced by any single agent. In an orthotopic breast cancer xenograft model (HCC1954), the growth of the tumour cells resumes after having achieved a complete response to T-DM1 treatment. Conversely, DHA and T-DM1 treatment induces a severe and irreversible cytotoxic effect, even after treatment interruption, thus, improving the long-term efficacy of T-DM1. These results suggest that DHA increases the effect of T-DM1 as poison for microtubules and supports the clinical development of the combination of DHA and T-DM1 for the treatment of aggressive HER2-overexpressing breast cancer.<\/jats:p>","DOI":"10.3390\/cells9051260","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T10:37:38Z","timestamp":1589971058000},"page":"1260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["DHA Affects Microtubule Dynamics Through Reduction of Phospho-TCTP Levels and Enhances the Antiproliferative Effect of T-DM1 in Trastuzumab-Resistant HER2-Positive Breast Cancer Cell Lines"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-4589","authenticated-orcid":false,"given":"Silvia","family":"D\u2019Amico","sequence":"first","affiliation":[{"name":"National Research Council of Italy, Institute of Translational Pharmacology (IFT-CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9137-5446","authenticated-orcid":false,"given":"Ewa","family":"Krasnowska","sequence":"additional","affiliation":[{"name":"National Research Council of Italy, Institute of Translational Pharmacology (IFT-CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Manni","sequence":"additional","affiliation":[{"name":"UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4182-2468","authenticated-orcid":false,"given":"Gabriele","family":"Toietta","sequence":"additional","affiliation":[{"name":"Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7982-9468","authenticated-orcid":false,"given":"Silvia","family":"Baldari","sequence":"additional","affiliation":[{"name":"Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Piaggio","sequence":"additional","affiliation":[{"name":"UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ranalli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \"Tor Vergata\", 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Gambacurta","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \"Tor Vergata\", 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1577-8176","authenticated-orcid":false,"given":"Claudio","family":"Vernieri","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"},{"name":"IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Di Giacinto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bernassola","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \"Tor Vergata\", 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"de Braud","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"},{"name":"Oncology and Hemato-Oncology Department, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-6338","authenticated-orcid":false,"given":"Maria","family":"Lucibello","sequence":"additional","affiliation":[{"name":"National Research Council of Italy, Institute of Translational Pharmacology (IFT-CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ccr.2014.02.025","article-title":"ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics","volume":"25","author":"Arteaga","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fonc.2018.00089","article-title":"Current Therapies for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Patients","volume":"8","author":"Larionov","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.critrevonc.2019.05.001","article-title":"Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: Current knowledge, new research directions and therapeutic perspectives","volume":"139","author":"Vernieri","year":"2019","journal-title":"Crit. Rev. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102458","DOI":"10.18632\/oncotarget.22270","article-title":"Efficacy and safety of trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancer (MBC): A meta-analysis of randomized controlled trial","volume":"8","author":"Yan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/S1470-2045(17)30312-1","article-title":"Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): A descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial","volume":"18","author":"Miles","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_6","first-page":"617","article-title":"Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer","volume":"380","author":"Huang","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1703643","article-title":"Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer","volume":"377","author":"Procter","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1158\/0008-5472.CAN-17-3671","article-title":"Resistance to Antibody\u2013Drug Conjugates","volume":"78","author":"Ocana","year":"2018","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1158\/1535-7163.MCT-17-0296","article-title":"Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells","volume":"17","author":"Li","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5275","DOI":"10.18632\/oncotarget.2971","article-title":"Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells","volume":"6","author":"Lucibello","year":"2015","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/978-3-319-67591-6_4","article-title":"The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation","volume":"64","author":"Bommer","year":"2017","journal-title":"Results Probl. Cell Differ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1091\/mbc.e07-02-0188","article-title":"A Knockout Mouse Approach Reveals that TCTP Functions as an Essential Factor for Cell Proliferation and Survival in a Tissue- or Cell Type\u2013specific Manner","volume":"18","author":"Chen","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1016\/j.yexcr.2011.07.012","article-title":"TCTP is a critical survival factor that protects cancer cells from oxidative stress-induced cell-death","volume":"317","author":"Lucibello","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1097\/CCO.0b013e32835b7d21","article-title":"Lessons from tumor reversion for cancer treatment","volume":"25","author":"Amson","year":"2013","journal-title":"Curr. Opin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14976","DOI":"10.1073\/pnas.222470799","article-title":"Biological models and genes of tumor reversion: Cellular reprogramming through tpt1\/TCTP and SIAH-1","volume":"99","author":"Tuynder","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nature05528","article-title":"Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase","volume":"445","author":"Hsu","year":"2007","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15364","DOI":"10.1073\/pnas.0406776101","article-title":"Translationally controlled tumor protein is a target of tumor reversion","volume":"101","author":"Tuynder","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.tcb.2012.10.002","article-title":"TPT1\/ TCTP-regulated pathways in phenotypic reprogramming","volume":"23","author":"Amson","year":"2013","journal-title":"Trends Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/978-3-319-67591-6_15","article-title":"Targeting TCTP with Sertraline and Thioridazine in Cancer Treatment","volume":"64","author":"Amson","year":"2017","journal-title":"Results Probl. Cell Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nm.2546","article-title":"Reciprocal repression between P53 and TCTP","volume":"18","author":"Amson","year":"2011","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8061","DOI":"10.1038\/srep08061","article-title":"Translationally Controlled Tumor Protein induces epithelial to mesenchymal transition and promotes cell migration, invasion and metastasis","volume":"5","author":"Bae","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.bbamcr.2017.09.014","article-title":"Translationally controlled tumor protein (TCTP) is required for TGF-\u03b21 induced epithelial to mesenchymal transition and influences cytoskeletal reorganization","volume":"1865","author":"Mishra","year":"2018","journal-title":"Biochim. et Biophys. Acta (BBA) - Bioenerg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3357","DOI":"10.1007\/s13277-013-0906-9","article-title":"TCTP overexpression is associated with the development and progression of glioma","volume":"34","author":"Miao","year":"2013","journal-title":"Tumor Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10735-014-9607-y","article-title":"Expression and clinical role of TCTP in epithelial ovarian cancer","volume":"46","author":"Chen","year":"2015","journal-title":"J. Mol. Histol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/978-3-319-67591-6_13","article-title":"TCTP Has a Crucial Role in the Different Stages of Prostate Cancer Malignant Progression","volume":"64","author":"Baylot","year":"2017","journal-title":"Results Probl. Cell Differ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/pros.21412","article-title":"TP53INP1 overexpression in prostate cancer correlates with poor prognostic factors and is predictive of biological cancer relapse","volume":"72","author":"Giusiano","year":"2011","journal-title":"Prostate"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.1038\/onc.2017.113","article-title":"Playing polo during mitosis: PLK1 takes the lead","volume":"36","author":"Combes","year":"2017","journal-title":"Oncogene"},{"key":"ref_28","first-page":"127","article-title":"Current Understanding of the TCTP Interactome","volume":"64","author":"Li","year":"2017","journal-title":"Plant Promot. Transcr. Factors"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1128\/MCB.25.8.3117-3126.2005","article-title":"Stabilization and Enhancement of the Antiapoptotic Activity of Mcl-1 by TCTP","volume":"25","author":"Liu","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6209","DOI":"10.1128\/MCB.22.17.6209-6221.2002","article-title":"Plk Phosphorylation Regulates the Microtubule-Stabilizing Protein TCTP","volume":"22","author":"Yarm","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_31","first-page":"4973","article-title":"Phosphorylation of TCTP as a marker for polo-like kinase-1 activity in vivo","volume":"30","author":"Cucchi","year":"2010","journal-title":"Anticancer. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.molcel.2018.05.026","article-title":"DNA Replication Determines Timing of Mitosis by Restricting CDK1 and PLK1 Activation","volume":"71","author":"Lemmens","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.bbamcr.2016.01.012","article-title":"TCTP regulates spindle microtubule dynamics by stabilizing polar microtubules during mouse oocyte meiosis","volume":"1863","author":"Jeon","year":"2016","journal-title":"Biochim. et Biophys. Acta (BBA) - Bioenerg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1242\/jcs.112.8.1257","article-title":"The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle","volume":"112","author":"Gachet","year":"1999","journal-title":"J. Cell Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1128\/AAC.45.8.2397-2399.2001","article-title":"Immunoprecipitation of [3H]Dihydroartemisinin Translationally Controlled Tumor Protein (TCTP) Adducts from Plasmodium falciparum-Infected Erythrocytes by Using Anti-TCTP Antibodies","volume":"45","author":"Bhisutthibhan","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.drup.2005.04.003","article-title":"Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy","volume":"8","author":"Efferth","year":"2005","journal-title":"Drug Resist. Updat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13046-017-0531-3","article-title":"Dihydroartemisinin inhibits TCTP-dependent metastasis in gallbladder cancer","volume":"36","author":"Zhang","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/nm.2471","article-title":"The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine","volume":"17","author":"Tu","year":"2011","journal-title":"Nat. Med."},{"key":"ref_39","first-page":"4417","article-title":"First study of oral Artenimol-R in advanced cervical cancer: Clinical benefit, tolerability and tumor markers","volume":"31","author":"Jansen","year":"2011","journal-title":"Anticancer. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1007\/s00228-014-1754-2","article-title":"Population pharmacokinetics of artesunate and dihydroartemisinin during long-term oral administration of artesunate to patients with metastatic breast cancer","volume":"70","author":"Ericsson","year":"2014","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s10549-017-4261-1","article-title":"Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33\/2)","volume":"164","author":"Goeckenjan","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/1475-2875-10-263","article-title":"Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration","volume":"10","author":"Duparc","year":"2011","journal-title":"Malar. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/1475-2875-13-281","article-title":"Pharmacokinetic evaluation of intravenous artesunate in adults with uncomplicated falciparum malaria in Kenya: A phase II study","volume":"13","author":"Li","year":"2014","journal-title":"Malar. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.molmed.2007.07.001","article-title":"From traditional Chinese medicine to rational cancer therapy","volume":"13","author":"Efferth","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.3727\/096368911X637452","article-title":"Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue","volume":"21","author":"Gentile","year":"2012","journal-title":"Cell Transplant."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1242\/dmm.028274","article-title":"In vivo models in breast cancer research: Progress, challenges and future directions","volume":"10","author":"Holen","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1200\/JCO.2014.60.0742","article-title":"Deciphering the Role of Phosphatidylinositol 3-Kinase Mutations in Human Epidermal Growth Factor Receptor 2\u2013Positive Breast Cancer","volume":"33","author":"Goel","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S1359-6349(09)70060-6","article-title":"57 A functional genetic approach identifies the PI3K pathway as a major determinant of Trastuzumab resistance in breast cancer","volume":"7","author":"Berns","year":"2009","journal-title":"Eur. J. Cancer Suppl."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1158\/1535-7163.MCT-09-1171","article-title":"Activated phosphoinositide 3-kinase\/AKT signaling confers resistance to trastuzumab but not lapatinib","volume":"9","author":"Browne","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_51","first-page":"135","article-title":"Population Pharmacokinetics of Artesunate and Dihydroartemisinin in Healthy Volunteers","volume":"79","author":"Tan","year":"2008","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1158\/1535-7163.MCT-11-0765","article-title":"NMS-P937, an Orally Available, Specific Small-Molecule Polo-like Kinase 1 Inhibitor with Antitumor Activity in Solid and Hematologic Malignancies","volume":"11","author":"Valsasina","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhang, S., and Gerhard, G.S. (2009). Heme Mediates Cytotoxicity from Artemisinin and Serves as a General Anti-Proliferation Target. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007472"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10928-010-9156-2","article-title":"Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice","volume":"37","author":"Jumbe","year":"2010","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Schwarz, L., Hutchinson, K.E., Rexer, B.N., Estrada, M.V., Gonzalez-Ericsson, P.I., Sanders, M.E., Dugger, T.C., Formisano, L., Guerrero-Zotano, A., and Red-Brewer, M. (2017). An ERBB1-3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression. J. Natl. Cancer Inst., 109.","DOI":"10.1093\/jnci\/djx065"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.ccr.2011.12.001","article-title":"Ligand-Independent HER2\/HER3\/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941","volume":"20","author":"Junttila","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1158\/1078-0432.CCR-13-0358","article-title":"Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy","volume":"20","author":"Phillips","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1158\/1541-7786.MCR-15-0068","article-title":"Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies","volume":"13","author":"Zadra","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5185","DOI":"10.1074\/jbc.RA117.001379","article-title":"Phosphorylation of CDC25C by AMP-activated protein kinase mediates a metabolic checkpoint during cell-cycle G2\/M-phase transition","volume":"293","author":"Shen","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1200\/JCO.2011.37.2482","article-title":"Clinically Used Breast Cancer Markers Such As Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Are Unstable Throughout Tumor Progression","volume":"30","author":"Karlsson","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1002\/jso.24762","article-title":"Change in HER2 status after neoadjuvant chemotherapy and the prognostic impact in patients with primary breast cancer","volume":"116","author":"Yoshida","year":"2017","journal-title":"J. Surg. Oncol."},{"key":"ref_62","first-page":"1","article-title":"Targeting the Mitotic Catastrophe Signaling Pathway in Cancer","volume":"2015","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.molcel.2015.01.034","article-title":"Biology of Poly(ADP-Ribose) Polymerases: The Factotums of Cell Maintenance","volume":"58","author":"Bai","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nrc1317","article-title":"Microtubules as a target for anticancer drugs","volume":"4","author":"Jordan","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_65","first-page":"1","article-title":"Clinical toxicities encountered with paclitaxel (Taxol)","volume":"20","author":"Rowinsky","year":"1993","journal-title":"Semin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"T83","DOI":"10.1530\/ERC-17-0003","article-title":"Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic","volume":"24","author":"Shi","year":"2017","journal-title":"Endocrine-Related Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1158\/0008-5472.CAN-14-2475","article-title":"Kinome-wide Functional Screen Identifies Role of PLK1 in Hormone-Independent, ER-Positive Breast Cancer","volume":"75","author":"Bhola","year":"2015","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1158\/1078-0432.CCR-09-1380","article-title":"Targeting Polo-like Kinase in Cancer Therapy","volume":"16","author":"Degenhardt","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1097\/PAS.0000000000000386","article-title":"Combined Immunohistochemistry of PLK1, p21, and p53 for Predicting TP53 Status","volume":"39","author":"Watanabe","year":"2015","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1038\/s41467-018-05429-5","article-title":"Plk1 overexpression induces chromosomal instability and suppresses tumor development","volume":"9","author":"Venkateswaran","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1158\/1535-7163.MCT-15-0897","article-title":"Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics","volume":"15","author":"Gutteridge","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1038\/s41388-017-0108-9","article-title":"Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2\/xL in HER2-positive breast cancer","volume":"37","author":"Saatci","year":"2018","journal-title":"Oncogene"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/541906","article-title":"Association of TCTP with Centrosome and Microtubules","volume":"2012","author":"Jaglarz","year":"2012","journal-title":"Biochem. Res. Int."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11060-015-1900-4","article-title":"High levels of polo-like kinase 1 and phosphorylated translationally controlled tumor protein indicate poor prognosis in neuroblastomas","volume":"125","author":"Ramani","year":"2015","journal-title":"J. Neuro-Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6084","DOI":"10.1158\/0008-5472.CAN-07-6854","article-title":"An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer","volume":"68","author":"Lluch","year":"2008","journal-title":"Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"382","DOI":"10.4048\/jbc.2018.21.e48","article-title":"PIK3CA Mutations and Neoadjuvant Therapy Outcome in Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: A Sequential Analysis","volume":"21","author":"Seo","year":"2018","journal-title":"J. Breast Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.clbc.2018.10.014","article-title":"Relapsed and De Novo Metastatic HER2-positive Breast Cancer Treated With Trastuzumab: Tumor Genotypes and Clinical Measures Associated With Patient Outcome","volume":"19","author":"Kotoula","year":"2019","journal-title":"Clin. Breast Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1158\/1078-0432.CCR-14-2993","article-title":"PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance","volume":"21","author":"Stern","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4951","DOI":"10.1242\/jcs.038083","article-title":"Centrosome positioning in vertebrate development","volume":"125","author":"Tang","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1007\/s00436-007-0671-z","article-title":"Translationally controlled tumor protein of Brugia malayi functions as an antioxidant protein","volume":"101","author":"Gnanasekar","year":"2007","journal-title":"Parasitol. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1158\/1535-7163.MCT-11-0534","article-title":"Artesunate Induces Oxidative DNA Damage, Sustained DNA Double-Strand Breaks, and the ATM\/ATR Damage Response in Cancer Cells","volume":"10","author":"Berdelle","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_82","first-page":"767","article-title":"The anti-malarial artesunate is also active against cancer","volume":"18","author":"Efferth","year":"2001","journal-title":"Int. J. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.trecan.2017.02.001","article-title":"Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities","volume":"3","author":"Bakhoum","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4309","DOI":"10.1158\/1078-0432.CCR-12-1424","article-title":"Molecular pathways: Reactive oxygen species homeostasis in cancer cells and implications for cancer therapy","volume":"19","author":"Nogueira","year":"2013","journal-title":"Clin. Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/5\/1260\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:30:28Z","timestamp":1760175028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/5\/1260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,19]]},"references-count":84,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["cells9051260"],"URL":"https:\/\/doi.org\/10.3390\/cells9051260","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,19]]}}}