{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T08:22:28Z","timestamp":1776586948319,"version":"3.51.2"},"posted":{"date-parts":[[2025,12,26]]},"group-title":"Pharmacology and Toxicology","reference-count":93,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["KL2 TR002015"],"award-info":[{"award-number":["KL2 TR002015"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38\u2212) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"696284v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.24.696284","type":"posted-content","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T18:35:22Z","timestamp":1766774122000},"source":"Crossref","is-referenced-by-count":1,"title":["CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins"],"prefix":"10.64898","author":[{"given":"Muhammad","family":"Daniyal","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajesh","family":"Rajaiah","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0519-7087","authenticated-orcid":false,"given":"Upendarrao","family":"Golla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marudhu Pandiyan","family":"Shanmugam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koby","family":"Duke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Mercer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasin","family":"Uzun","sequence":"additional","affiliation":[{"name":"Department of Molecular and Precision Medicine, Penn State Cancer Institute, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Valensi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Precision Medicine, Penn State Cancer Institute, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Hengst","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"},{"name":"Department of Molecular and Precision Medicine, Penn State Cancer Institute, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinisa","family":"Dovat","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Cell and Biological Systems, Penn State Cancer Institute, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suming","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandrika G","family":"Behura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025123008400774000_2025.12.24.696284v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21442"},{"key":"2025123008400774000_2025.12.24.696284v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-020-00711-3"},{"key":"2025123008400774000_2025.12.24.696284v1.3","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21590"},{"key":"2025123008400774000_2025.12.24.696284v1.4","doi-asserted-by":"crossref","unstructured":"Fleischmann, M. , et al., Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives. 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