{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:09:48Z","timestamp":1783922988257,"version":"3.55.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Paclitaxel-based chemotherapy remains a mainstay for breast cancer treatment, yet its efficacy is often limited by drug resistance and dose-limiting peripheral neuropathy. This study aimed to investigate whether CDK8 could serve as a dual target for enhancing the antitumor efficacy of paclitaxel while alleviating chemotherapy-induced neuropathic pain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated CDK8 expression in human breast cancer specimens before and after paclitaxel-containing neoadjuvant chemotherapy, as well as in paclitaxel-treated breast cancer cell lines and DRGs from syngeneic tumor-bearing mice. Loss- and gain-of-function approaches were performed to assess the functional role of CDK8 in tumor growth, paclitaxel sensitivity, and neuropathic pain behaviors. Myelin damage in the sciatic nerve was evaluated by transmission electron microscopy via G-ratio quantification. Finally, the selective CDK8\/CDK19 inhibitor romaciclib was tested for its ability to enhance paclitaxel antitumor efficacy and alleviate paclitaxel induced peripheral neuropathy in a 4T1 murine breast cancer model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CDK8 expression was markedly upregulated in human post-chemotherapy breast cancer tissues, paclitaxel-treated breast cancer cells, and DRGs of tumor-bearing mice. CDK8 overexpression promoted tumor growth and paclitaxel resistance, while CDK8 knockdown sensitized tumors to chemotherapy. In the peripheral nervous system, elevated CDK8 in DRGs recapitulated paclitaxel-induced mechanical allodynia, thermal hyperalgesia, and myelin damage, whereas CDK8 depletion prevented these neurotoxic effects. Pharmacological inhibition of CDK8 with romaciclib not only enhanced the antitumor efficacy of paclitaxel but also significantly alleviated paclitaxel-induced peripheral neuropathy\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CDK8 is a dual target linking chemoresistance and neurotoxicity. Inhibiting CDK8 with romaciclib may improve paclitaxel therapy while reducing its side effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1849893","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:32:54Z","timestamp":1783920774000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting CDK8 dually enhances paclitaxel antitumor efficacy and alleviates chemotherapy-induced peripheral neuropathy in breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Xuejiao","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]},{"name":"Institute of Chemical Biology, School of Pharmacy, Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Fang","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, School of Pharmacy, Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"100918","DOI":"10.1016\/j.ctarc.2025.100918","article-title":"Paclitaxel resistance in breast cancer: current challenges and recent advanced therapeutic strategies","volume":"43","author":"Abouzeid","year":"2025","journal-title":"Cancer Treat. Res. Commun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s40487-021-00168-y","article-title":"Chemotherapy-induced peripheral neuropathy: epidemiology, pathomechanisms and treatment","volume":"9","author":"Burgess","year":"2021","journal-title":"Oncol. Ther."},{"key":"B3","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.biopha.2015.08.015","article-title":"Downregulation of CDK-8 inhibits colon cancer hepatic metastasis by regulating Wnt\/\u03b2-catenin pathway","volume":"74","author":"Cai","year":"2015","journal-title":"Biomed. Pharmacother."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1097\/j.pain.0000000000003577","article-title":"Ribosome profiling reveals that post-transcriptional control of by heterogeneous nuclear ribonucleoprotein L is required for paclitaxel-induced neuropathic pain","volume":"166","author":"de la Pe\u00f1a","year":"2025","journal-title":"Pain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e2201073119","DOI":"10.1073\/pnas.2201073119","article-title":"Inhibition of CDK8\/19 mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo","volume":"119","author":"Ding","year":"2022","journal-title":"P Natl. Acad. Sci. U. S. A."},{"key":"B6","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nature07179","article-title":"CDK8 is a colorectal cancer oncogene that regulates \u03b2-catenin activity","volume":"455","author":"Firestein","year":"2008","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.1038\/s41388-021-01745-1","article-title":"CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway","volume":"40","author":"Fukasawa","year":"2021","journal-title":"Oncogene"},{"key":"B8","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s41420-025-02339-6","article-title":"CDK8\/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells","volume":"11","author":"Khamidullina","year":"2025","journal-title":"Cell Death Discov."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.3390\/ijms27052109","article-title":"The future of breast cancer treatment: from conventional wisdom to nanotechnology-enabled precision","volume":"27","author":"Kimta","year":"2026","journal-title":"Int. J. Mol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1038\/s41419-021-04279-2","article-title":"Triple-negative breast cancer cells rely on kinase-independent functions of CDK8 to evade NK-cell-mediated tumor surveillance","volume":"12","author":"Knab","year":"2021","journal-title":"Cell Death Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e176709","DOI":"10.1172\/jci176709","article-title":"Mediator kinase inhibition reverses castration resistance of advanced prostate cancer","volume":"134","author":"Li","year":"2024","journal-title":"J. Clin. Invest."},{"key":"B12","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1021\/acs.jcim.4c02011","article-title":"Identification of a potent CDK8 inhibitor using structure-based virtual screening","volume":"65","author":"Lin","year":"2024","journal-title":"J. Chem. Inf. Model"},{"key":"B13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.jare.2025.01.017","article-title":"CDK8 mediated inflammatory microenvironment aggravates osteoarthritis progression","volume":"77","author":"Lin","year":"2025","journal-title":"J. Adv. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.cub.2017.01.056","article-title":"The CDK8 complex and proneural proteins together drive neurogenesis from a mesodermal lineage","volume":"27","author":"Luo","year":"2017","journal-title":"Curr. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1080\/15384101.2025.2575050","article-title":"The dual role of circular RNAs in paclitaxel resistance: insights into molecular mechanisms and clinical implications","volume":"24","author":"Maghrebi-Ghojogh","year":"2025","journal-title":"Cell Cycle"},{"key":"B16","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.celrep.2013.07.012","article-title":"CDK8-Mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance","volume":"4","author":"Putz","year":"2013","journal-title":"Cell Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"172714","DOI":"10.1016\/j.ejphar.2019.172714","article-title":"Pharmacological interventions targeting Wnt\/\u03b2-catenin signaling pathway attenuate paclitaxel-induced peripheral neuropathy","volume":"864","author":"Resham","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"107534","DOI":"10.1016\/j.phrs.2024.107534","article-title":"Targeted and cytotoxic inhibitors used in the treatment of breast cancer","volume":"210","author":"Roskoski","year":"2024","journal-title":"Pharmacol. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1016\/j.bbapap.2015.05.011","article-title":"CDK8 kinase-An emerging target in targeted cancer therapy","volume":"1854","author":"Rzymski","year":"2015","journal-title":"Bba-Proteins Proteom"},{"key":"B20","doi-asserted-by":"publisher","first-page":"33779","DOI":"10.18632\/oncotarget.16810","article-title":"SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains","volume":"8","author":"Rzymski","year":"2017","journal-title":"Oncotarget"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3827","DOI":"10.21873\/anticanres.17742","article-title":"Paclitaxel-induced peripheral neuropathy and quality of life: sub-analysis of the MICHEL study","volume":"45","author":"Sawa","year":"2025","journal-title":"Anticancer Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/s11302-025-10120-8","article-title":"Spinal P2X receptors blockade reverses paclitaxel-induced allodynia in rats","volume":"22","author":"Segura-Chama","year":"2026","journal-title":"Purinerg Signal"},{"key":"B23","doi-asserted-by":"publisher","first-page":"6141","DOI":"10.1038\/s44319-025-00534-1","article-title":"Proneurotrophin-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons","volume":"26","author":"Sharma","year":"2025","journal-title":"Embo Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s12943-024-02067-y","article-title":"Targeting DKK1 enhances the antitumor activity of paclitaxel and alleviates chemotherapy-induced peripheral neuropathy in breast cancer","volume":"23","author":"Shi","year":"2024","journal-title":"Mol. Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"113121","DOI":"10.1016\/j.expneurol.2019.113121","article-title":"Pathogenesis of paclitaxel-induced peripheral neuropathy: a current review of in vitro and in vivo findings using rodent and human model systems","volume":"324","author":"Staff","year":"2020","journal-title":"Exp. Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1007\/s12640-022-00582-8","article-title":"Neurophysiopathological aspects of paclitaxel-induced peripheral neuropathy","volume":"40","author":"Velasco-Gonz\u00e1lez","year":"2022","journal-title":"Neurotox. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"11152","DOI":"10.1038\/s41467-025-64937-3","article-title":"Transcriptional regulation of protein synthesis by mediator kinase represents a therapeutic vulnerability in MYC-driven medulloblastoma","volume":"16","author":"Wang","year":"2025","journal-title":"Nat. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"479","DOI":"10.4093\/dmj.2024.0809","article-title":"Exosomal Circ_STAT1-AS delivery induced by dexmedetomidine modulates microglial polarization to alleviate diabetic peripheral neuropathy by JAK\/STAT1","volume":"50","author":"Wei","year":"2026","journal-title":"Diabetes Metab. J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1038\/s41388-026-03710-2","article-title":"CDK8 phosphorylates SOX2 to maintain stemness of pituitary adenoma","volume":"45","author":"Xie","year":"2026","journal-title":"Oncogene"},{"key":"B30","doi-asserted-by":"publisher","first-page":"8161","DOI":"10.1021\/acs.jmedchem.4c00248","article-title":"Discovery of a novel and potent cyclin-dependent kinase 8\/19 (CDK8\/19) inhibitor for the treatment of cancer","volume":"67","author":"Xu","year":"2024","journal-title":"J. Med. Chem."},{"key":"B31","first-page":"7236","article-title":"miR-107 regulates cisplatin chemosensitivity of A549 non small cell lung cancer cell line by targeting cyclin dependent kinase 8","volume":"7","author":"Zhang","year":"2014","journal-title":"Int. J. Clin. Exp. Patho"},{"key":"B32","doi-asserted-by":"publisher","first-page":"E6760","DOI":"10.1073\/pnas.1800621115","article-title":"Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation","volume":"115","author":"Zhou","year":"2018","journal-title":"P Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1849893\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:32:55Z","timestamp":1783920775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1849893\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":32,"alternative-id":["10.3389\/fphar.2026.1849893"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1849893","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]},"article-number":"1849893"}}