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Increasing evidence highlights CDK9\u2019s involvement in transcriptional addiction in cancer. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We explored the efficacy and mechanism of action of novel CDK9 inhibitors, alone or in combination with EGFR inhibitors, using TNBC cell lines and in vivo xenograft models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Targeting CDK9 significantly impaired proliferation and induced apoptosis in multiple TNBC cell lines. Transcriptomic analyses revealed that CDK9 inhibitors induced downregulation of genes involved in transcription, cell cycle progression, and oncogenic signalling pathways, including TGF-\u03b2 and Wnt\/\u03b2-catenin signalling. Combined CDK9 and EGFR inhibition disrupted transcriptional programs, enhanced TNBC cell death in vitro, and acted synergistically to reduce tumour growth in PDX and Hs578T xenograft models, although this combination was also associated with increased toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s13402-025-01154-6","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T11:50:53Z","timestamp":1767873053000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Disrupting CDK9 activity suppresses triple-negative breast cancer and is enhanced by EGFR Inhibition"],"prefix":"10.1007","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9894-3239","authenticated-orcid":false,"given":"Vera E.","family":"van der Noord","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronan P.","family":"McLaughlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica S.","family":"Karuntu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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The TMAs used in this study were previously generated [\n                      \n                      ]. Their generation was approved by the Medical Ethics Committee of the Erasmus Medical Center, The Netherlands (MEC 02.953), and was conducted in accordance with the Declaration of Helsinki and the Code of Conduct of the Federation of Medical Scientific Societies in The Netherlands. Informed consent was obtained from all patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"S.W., S.A.H.D., S.T. and Y.L. have patents related to the CDK9 and CDK4\/6 inhibitors used in this study. The authors declare no further competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20"}}