{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:48:43Z","timestamp":1790938123492,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The PIM family of serine\/threonine kinases (PIM1, PIM2, and PIM3) are involved in the development of cancer and represent promising therapeutic targets. We investigated the therapeutic potential of targeting PIM kinases in diffuse large B\u2010cell lymphoma (DLBCL), particularly the activated B\u2010cell\u2010like (ABC) subtype, using the pan\u2010PIM inhibitor AZD1208. We demonstrated that PIM1 and PIM2 are more highly expressed in ABC\u2010 cells than in germinal center B\u2010cell\u2010like (GCB) \u2010DLBCL cells, and that ABC\u2010DLBCL cell lines are more sensitive to PIM inhibition with AZD1208. Transcriptome analysis of ABC\u2010DLBCL cell lines treated with AZD1208 revealed a downregulation of genes involved in NF\u2010\u03baB signaling, a crucial pathway for ABC\u2010DLBCL. We also explored synergistic drug combinations using a high\u2010throughput screen, which identified BCL2 and glutaminase inhibitors as effective partners for AZD1208, particularly in aggressive ABC\u2010DLBCL and double\u2010hit cell lines. The combination of AZD1208 with the clinically available BCL2 inhibitor venetoclax was synergistic in most DLBCL cell lines, and this combination induced apoptosis and reduced levels of AKT and MCL1 proteins. In conclusion, our findings suggested that AZD1208, especially when combined with BCL2 inhibitors like venetoclax, holds promise as a treatment strategy for aggressive lymphomas. These combinations may enable lower doses of PIM inhibitors, leading to increased tolerability and improved anti\u2010tumor activity in clinical settings. The study also highlighted the potential for targeting PIM kinases in combination with other therapies to overcome drug resistance in DLBCL.<\/jats:p>","DOI":"10.1002\/hon.70055","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T12:58:35Z","timestamp":1741438715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting of PIM Kinases Shows Single Agent Efficacy and Synergizes With BCL2 Inhibitors in Diffuse Large B Cell Lymphoma of the ABC Subtype"],"prefix":"10.1002","volume":"43","author":[{"given":"Chiara","family":"Tarantelli","sequence":"first","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6642-2463","authenticated-orcid":false,"given":"Omar","family":"Kayali","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Civanelli","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Cascione","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"},{"name":"SIB Swiss Institute of Bioinformatics  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8113-3689","authenticated-orcid":false,"given":"Afua Adjeiwaa","family":"Mensah","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Folloni","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto J.","family":"Arribas","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"},{"name":"SIB Swiss Institute of Bioinformatics  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Cmiljanovic","sequence":"additional","affiliation":[{"name":"Torqur AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Mondello","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"},{"name":"Division of Hematology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-8983","authenticated-orcid":false,"given":"Francesco","family":"Bertoni","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Faculty of Biomedical Sciences USI  Bellinzona Switzerland"},{"name":"Oncology Institute of Southern Switzerland Ente Ospedaliero Cantonale  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010023\u201001721\u20101"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2009.017079"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010014\u20100095\u2010z"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.123"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.174"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.107454"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom8010007"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmra2027612"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12957\u2010023\u201002947\u20105"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb1945oia9"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201013\u20102062"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102011\u201003\u2010344374"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1732008100"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1801445"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010018\u20100016\u20108"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.027"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277\u2010024\u201005670\u20107"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.can\u201021\u20101023"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.targ\u201023\u2010c144"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201017\u20101041"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11457"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010015\u20100477\u2010z"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0199108"},{"issue":"11","key":"e_1_2_10_25_1","first-page":"2489","article-title":"The Role of PIM1 in the Ibrutinib\u2010Resistant ABC Subtype of Diffuse Large B\u2010Cell Lymphoma","volume":"6","author":"Kuo H. P.","year":"2016","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2020.1795156"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2023.05.002"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010018\u20100082\u20101"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185\u2010021\u201003096\u20109"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/2767\u20109764.crc\u201022\u20100477"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201014\u20101561"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201018\u20102718"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201002595\u2010w"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201006354\u20103"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018020602"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/0-387-29362-0_23"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.055"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.05.098"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806928115"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102013\u201006\u2010508937"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11223700"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15204957"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.06.050"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m307933200"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.can\u201005\u20104272"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13092139"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v126.23.5120.5120"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010067"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1013214108"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201018\u20100706"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.am2014\u20101416"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201022\u20100061"}],"container-title":["Hematological Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hon.70055","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T03:51:42Z","timestamp":1760413902000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/hon.70055"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":52,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/hon.70055"],"URL":"https:\/\/doi.org\/10.1002\/hon.70055","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/HON.70055\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v3\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.70055\/v3\/decision1","asserted-by":"object"}]},"ISSN":["0278-0232","1099-1069"],"issn-type":[{"value":"0278-0232","type":"print"},{"value":"1099-1069","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"2024-04-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70055"}}