{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:15:54Z","timestamp":1790356554582,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014337","name":"Menarini Group","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>MEN1703 is a first\u2010in\u2010class, oral, Type I dual PIM\/FMS\u2010like tyrosine kinase 3 inhibitor (FLT3i) investigated in a Phase I\/II DIAMOND\u201001 trial in patients with acute myeloid leukaemia (AML). Gilteritinib is a highly potent and selective oral FLT3i approved for the treatment of relapsed\/refractory AML with FLT3 mutations. Although gilteritinib showed strong single\u2010agent activity in FLT3\u2010mutated AML, the development of gilteritinib resistance limits response durability, indicating the importance of novel combination strategies to improve disease outcome. PIM kinases govern FLT3\u2010ITD signalling and increased PIM kinase expression is found in samples from AML patients relapsing on FLT3i. Here, we report that the simultaneous inhibition of PIM and FLT3, through the combination of MEN1703 and gilteritinib, can consistently improve the in\u00a0vitro\/in vivo antitumor activity over the single agents, demonstrating the benefit of this combination. Moreover, we demonstrate that resistance to gilteritinib can be circumvented by combining MEN1703 with gilteritinib. MEN1703 interferes with FLT3 upregulation, Mcl\u20101 overexpression and PIM kinase signalling, which are all involved in FLT3i resistance. We also show that MEN1703 downregulates stromal cytokines that promote cytokine\u2010mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment\u2010mediated resistance to FLT3 inhibitors.<\/jats:p>","DOI":"10.1111\/jcmm.70235","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T03:35:42Z","timestamp":1733801742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Dual <scp>PIM<\/scp>\/<scp>FLT3<\/scp> Inhibitor <scp>MEN1703<\/scp> Combines Synergistically With Gilteritinib in <scp>FLT3<\/scp>\u2010<scp>ITD<\/scp>\u2010Mutant Acute Myeloid Leukaemia"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1240-8057","authenticated-orcid":false,"given":"Sonia","family":"Zicari","sequence":"first","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Merlino","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Paoli","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Fiascarelli","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Tunici","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Bisignano","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Belli","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clelia","family":"Irrissuto","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Talucci","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cirigliano","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Iannitto","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Bigioni","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bressan","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Brz\u00f3zka","sequence":"additional","affiliation":[{"name":"Ryvu Therapeutics  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3955-7944","authenticated-orcid":false,"given":"Gabriel","family":"Ghiaur","sequence":"additional","affiliation":[{"name":"Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Bellarosa","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Binaschi","sequence":"additional","affiliation":[{"name":"Menarini Group Preclinical and Translational Sciences  Pomezia Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-02-0492"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0422"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403099"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4271"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.06.003"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-186605"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/hematolrep15020035"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2021.100905"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24747"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1629"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018029850"},{"issue":"8","key":"e_1_2_10_13_1","article-title":"Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia","volume":"8","author":"Eguchi M.","year":"2020","journal-title":"Biomedicine"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-150277"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14298"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605642"},{"key":"e_1_2_10_17_1","unstructured":"EUR\u2010Lex \u201cDirective 2010\/63\/Eu of The European Parliament and of the Council of 22 September 2010 on the Protection of Animals Used for Scientific Purposes \u201d2010Official Journal of the European Union L 276 https:\/\/eur\u2010lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2010:276:0033:0079:en:PDF."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-8152-9"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00433-3"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-745133"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00502-7"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.22926"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12640"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3114"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500221"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21041537"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-023-02086-6"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-266742"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0876"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.70235","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T10:17:38Z","timestamp":1735208258000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.70235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":28,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1111\/jcmm.70235"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.70235","archive":["Portico"],"relation":{},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"value":"1582-1838","type":"print"},{"value":"1582-4934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12]]},"assertion":[{"value":"2024-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70235"}}