{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:55:40Z","timestamp":1787496940538,"version":"build-2736575974"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Steve and Nancy Fox Cancer Research Fund"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biomark Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Inhibitors of Bruton\u2019s tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including\n                    <jats:italic>de novo<\/jats:italic>\n                    synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation.\n                  <\/jats:p>","DOI":"10.1186\/s40364-024-00589-7","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T20:02:17Z","timestamp":1718654537000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The CDK9 inhibitor enitociclib overcomes resistance to BTK inhibition and CAR-T therapy in mantle cell lymphoma"],"prefix":"10.1186","volume":"12","author":[{"given":"Vivian","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianci","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsong","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"McIntosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovanny","family":"Vargas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"issue":"16","key":"589_CR1","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1182\/blood-2018-03-791392","volume":"132","author":"K Maddocks","year":"2018","unstructured":"Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647\u201356.","journal-title":"Blood"},{"issue":"6","key":"589_CR2","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1056\/NEJMoa1306220","volume":"369","author":"ML Wang","year":"2013","unstructured":"Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507\u201316.","journal-title":"N Engl J Med"},{"issue":"10121","key":"589_CR3","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/S0140-6736(17)33108-2","volume":"391","author":"M Wang","year":"2018","unstructured":"Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659\u201367.","journal-title":"Lancet"},{"issue":"21","key":"589_CR4","doi-asserted-by":"publisher","first-page":"3148","DOI":"10.1182\/blood.2021014162","volume":"139","author":"YQ Song","year":"2022","unstructured":"Song YQ, Zhou KS, Zou DH, Zhou JF, Hu JD, Yang HY, et al. Zanubrutinib in relapsed\/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. 2022;139(21):3148\u201358.","journal-title":"Blood"},{"issue":"Suppl 1","key":"589_CR5","doi-asserted-by":"publisher","first-page":"9368","DOI":"10.1182\/blood-2022-159425","volume":"140","author":"ML Wang","year":"2022","unstructured":"Wang ML, Shah NN, Jurczak W, Zinzani PL, Eyre TA, Cheah CY, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed\/refractory mantle cell lymphoma: additional patients and extended follow-up from the phase 1\/2 BRUIN study. Blood. 2022;140(Suppl 1):9368\u201372.","journal-title":"Blood"},{"issue":"14","key":"589_CR6","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1056\/NEJMoa1914347","volume":"382","author":"M Wang","year":"2020","unstructured":"Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331\u201342.","journal-title":"N Engl J Med"},{"key":"589_CR7","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/1471-2407-8-106","volume":"8","author":"S Blenk","year":"2008","unstructured":"Blenk S, Engelmann JC, Pinkert S, Weniger M, Schultz J, Rosenwald A, et al. Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis. BMC Cancer. 2008;8:106.","journal-title":"BMC Cancer"},{"issue":"2","key":"589_CR8","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/S1535-6108(03)00028-X","volume":"3","author":"A Rosenwald","year":"2003","unstructured":"Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3(2):185\u201397.","journal-title":"Cancer Cell"},{"issue":"1","key":"589_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s40164-024-00484-9","volume":"13","author":"F Yan","year":"2024","unstructured":"Yan F, Jiang V, Jordan A, Che Y, Liu Y, Cai Q, et al. The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma. Exp Hematol Oncol. 2024;13(1):14.","journal-title":"Exp Hematol Oncol"},{"issue":"4","key":"589_CR10","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1158\/1078-0432.CCR-19-1853","volume":"26","author":"J Cidado","year":"2020","unstructured":"Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. 2020;26(4):922\u201334.","journal-title":"Clin Cancer Res"},{"issue":"16","key":"589_CR11","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1182\/blood-2018-03-791392","volume":"132","author":"M Byrne","year":"2018","unstructured":"Byrne M, Frattini MG, Ottmann OG, Mantzaris I, Wermke M, Lee DJ, et al. Phase I study of the PTEFb inhibitor BAY 1251152 in patients with acute myelogenous leukemia. Blood. 2018;132(16):1647\u201356.","journal-title":"Blood"},{"issue":"15","key":"589_CR12","doi-asserted-by":"publisher","first-page":"7538","DOI":"10.1200\/JCO.2021.39.15_suppl.7538","volume":"39","author":"V Moreno","year":"2021","unstructured":"Moreno V, Cordoba R, Morillo D, Diamond JR, Hamdy AM, Izumi R, et al. Safety and efficacy of VIP152, a CDK9 inhibitor, in patients with double-hit lymphoma (DHL). J Clin Oncol. 2021;39(15):7538.","journal-title":"J Clin Oncol"}],"container-title":["Biomarker Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40364-024-00589-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40364-024-00589-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40364-024-00589-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T20:12:24Z","timestamp":1718655144000},"score":1,"resource":{"primary":{"URL":"https:\/\/biomarkerres.biomedcentral.com\/articles\/10.1186\/s40364-024-00589-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,18]]},"references-count":12,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["589"],"URL":"https:\/\/doi.org\/10.1186\/s40364-024-00589-7","relation":{},"ISSN":["2050-7771"],"issn-type":[{"value":"2050-7771","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,18]]},"assertion":[{"value":"31 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The patient samples were collected from peripheral blood, bone marrow, or apheresis after obtaining informed consent and approval from the Institutional Review Board at The University of Texas MD Anderson Cancer Center. All animal experimental procedures and protocols were approved by the Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center. According to this protocol, the maximal tumor size should be limited to 20\u00a0mm, which was not exceeded in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MW has the following potential competing interests: Consultancy: AbbVie, Acerta Pharma, ADC Therapeutics America, Amphista Therapeutics Limited, AstraZeneca, Be Biopharma, BeiGene, BioInvent, Bristol Myers Squibb, Deciphera, DTRM Biopharma (Cayman) Limited, Genentech, InnoCare, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Lilly, Merck, Miltenyi Biomedicine, Milken Institute, Oncternal, Parexel, Pepromene Bio, Pharmacyclics, VelosBio. Research: Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio, Vincerx. Honoraria: AbbVie, Acerta Pharma, AstraZeneca, Bantam Pharmaceutical, BeiGene, BioInvent, Bristol Myers Squibb, CAHON, Dava Oncology, Eastern Virginia Medical School, Genmab, i3Health, ICML, IDEOlogy Health, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Medscape, Meeting Minds Experts, MD Education, MJH Life Sciences, Merck, Moffit Cancer Center, NIH, Nurix, Oncology Specialty Group, OncLive, Pharmacyclics, Physicians Education Resources (PER), Practice Point Communications (PPC), Scripps, Studio ER Congressi, WebMD. No other authors have potential competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"62"}}