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However, its efficacy is often compromised by dose-limiting haematologic toxicities. Recent strategies aim to enhance chemotherapy tolerability while preserving its effectiveness. One emerging approach involves selective CDK4 inhibitors to serve as myeloid-protective agents in retinoblastoma (RB)-negative tumours, such as triple-negative breast cancer (TNBC). Because bone marrow (BM) cells rely on RB for proliferation, CDK4 inhibitors may protect these cells while sparing RB-deficient tumour cells. The present study investigated the potential of AU2\u201394, a first-in-class CDK4 inhibitor, to protect BM cells during myelosuppressive chemotherapy in TNBC, beyond its established application in RB-positive cancers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This study employed in vitro, ex vivo, and in vivo experiments to evaluate the myeloid-protective effects of AU2\u201394 against chemotherapy-induced damage.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>AU2\u201394\u00a0induced a transient G1 arrest that protects BM cells from chemotherapy-induced apoptosis by preventing DNA double-strand breaks. Pre-treatment with AU2\u201394 prior to 5-fluorouracil (5-FU) administration reduced BM cells apoptosis, preserved Ki67-positive cells, and mitigated declines in red blood cells and neutrophils. Similarly, AU2\u201394 pre-treatment before cisplatin administration reduced cisplatin-induced haematologic toxicity in RB-deficient TNBC bearing mice without compromising the efficacy of chemotherapy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These findings support the repurposing of AU2\u201394 as a myeloprotective agent, highlighting its therapeutic potential in RB-deficient tumours. With AU2\u201394 advancing to clinical trials, these results underscore its broader therapeutic promise, extending to both RB-positive and RB-negative cancer treatment.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical abstract<\/jats:title>\n            <jats:p>Schematic representation of the proposed mechanism by which AU2\u201394 preserves bone marrow cells from cisplatin-induced toxicity in RB-deficient cancer. (A) DNA-damaging chemotherapeutic drugs like cisplatin induce tumour cell death and provoke double-strand DNA damage in rapidly proliferating cells, including bone marrow (BM) cells, leading to unwanted myelosuppression. (B) Pre-administration of the selective CDK4 inhibitor AU2\u201394 before cisplatin induces transient G1 arrest in BM cells, a phase critical for monitoring DNA integrity. This intervention prevents chemotherapy-induced double-strand DNA damage in BM cells, thereby aiding in myelopreservation. Given that TNBC-derived tumour cells often carry genetic mutations in the retinoblastoma (RB) protein, these cells are resistant to CDK4 inhibition. Hence, the addition of AU2\u201394 to a cisplatin regimen does not interfere with treatment outcomes but solely functions as a myelopreservation strategy.\n<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s10637-025-01550-7","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:20:34Z","timestamp":1749169234000},"page":"728-741","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A novel CDK4 inhibitor for myeloid protection in chemotherapy-treated triple-negative breast Cancer"],"prefix":"10.1007","volume":"43","author":[{"given":"Ava","family":"Safaroghli-azar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laychiluh B","family":"Mekonnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Hassankhani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimma","family":"Lenjisa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita KC","family":"Basnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajer","family":"Batayneh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed H","family":"Rahaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shudong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"1550_CR1","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nrclinonc.2016.66","volume":"13","author":"G Bianchini","year":"2016","unstructured":"Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L (2016) Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. 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Wang reports a relationship with Aucentra Therapeutics Pty. Ltd., that includs: funding grants. S. Wang reports a relationship with Changzhou LeSun Pharmaceuticals Ltd. that includs: funding grants. S. Wang reports a relationship with Changzhou Qianhong Biopharmaceuticals Co. Ltd. that includs: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.The remaining authors have no relevant financial or non-financial interests to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}