{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T15:48:24Z","timestamp":1788623304976,"version":"build-2803163510"},"reference-count":65,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T00:00:00Z","timestamp":1686355200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Constitutive activation of the PI3K\/AKT\/mTOR\u2010pathway plays an important role in the pathogenesis of mantle cell lymphoma (MCL), leading to approval of the mTOR inhibitor temsirolimus for relapsed or refractory MCL. Yet, despite favorable initial response rates, early relapses under treatment have been observed. Therefore, understanding the underlying mechanisms of temsirolimus resistance and developing strategies to overcome it is highly warranted. Here, we established a new temsirolimus\u2010resistant MCL cell line to evaluate the molecular background of resistance to this drug. Transcriptome profiling and gene set enrichment analysis comparing temsirolimus\u2010sensitive and \u2010resistant cell lines showed significant upregulation of PI3K\/AKT\/mTor\u2010, RAS signaling\u2010 and the RTK\u2010dependent PDGFR\u2010, FGFR\u2010, Met\u2010 and ALK\u2010signaling\u2010pathways in the resistant cells. Furthermore,\n                    <jats:italic>MET<\/jats:italic>\n                    , known as important proto\u2010oncogene and mediator of drug resistance, was among the most upregulated genes in the resistant cells. Importantly, Met protein was overexpressed in both, MCL cells with acquired as well as intrinsic temsirolimus resistance, but could not be detected in any of the temsirolimus sensitive ones. Combined pharmacological inhibition of mTOR and Met signaling with temsirolimus and the RTK inhibitor crizotinib significantly restored sensitivity to temsirolimus. Furthermore, this combined treatment proved to be synergistic in all MCL cell lines investigated and was also active in primary MCL cells. In summary, we showed for the first time that overexpression of\n                    <jats:italic>MET<\/jats:italic>\n                    plays an important role for mediating temsirolimus resistance in MCL and combined treatment with temsirolimus and crizotinib is a very promising therapeutic approach for MCL and an effective strategy to overcome temsirolimus resistance.\n                  <\/jats:p>","DOI":"10.1002\/hon.3194","type":"journal-article","created":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T03:23:40Z","timestamp":1686367420000},"page":"858-868","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus"],"prefix":"10.1002","volume":"41","author":[{"given":"Marie","family":"Moosburner","sequence":"first","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamija","family":"Alibegovic","sequence":"additional","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5907-6841","authenticated-orcid":false,"given":"Korbinian","family":"Hasselmann","sequence":"additional","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Gaiderov","sequence":"additional","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Philippou\u2010Massier","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Genome Analysis (LAFUGA) Gene Center University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Blum","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Genome Analysis (LAFUGA) Gene Center University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2444-416X","authenticated-orcid":false,"given":"Luca","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Medicine III LMU University Hospital Gro\u00dfhadern of the Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Dreyling","sequence":"additional","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"},{"name":"Department of Medicine III LMU University Hospital Gro\u00dfhadern of the Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2676-0860","authenticated-orcid":false,"given":"Elisabeth","family":"Silkenstedt","sequence":"additional","affiliation":[{"name":"Department of Medicine III Laboratory for Experimental Leukemia and Lymphoma Research (ELLF) Ludwig\u2010Maximilians\u2010University  Munich Germany"},{"name":"Department of Medicine III LMU University Hospital Gro\u00dfhadern of the Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx223"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24797"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.14122.1"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2230"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102007\u201007\u2010103481"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102006\u201004\u2010015586"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2013.00165"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010009\u20100163\u20107"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2019.03.003"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(00)00114\u20108"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2664"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3860"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.01.001"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/hs9.0000000000000398"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2014.05.004"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2019.02.003"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2007.03.003"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.cd\u201012\u20100012"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107522"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102006\u201006\u2010030833"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102010\u201004\u2010189977"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2005.13.466"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2008.20.7977"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beha.2012.04.008"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci34739"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.cd\u201011\u20100085"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.02.005"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.62752"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2011.03.006"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210422"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210421"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2780"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010013\u20100886\u20107"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113008"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.can\u201020\u20101192"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2012.01.004"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a001115"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.3120"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/1478\u2010811x\u201011\u201097"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci28984"},{"issue":"1","key":"e_1_2_9_42_1","first-page":"13","article-title":"c\u2010Met as a target for personalized therapy","volume":"7","author":"Garajov\u00e1 I","year":"2015","journal-title":"Transl Oncogenomics"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2018.00086"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2012.71"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.12.014"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30437"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.13687"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2530"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476\u20104598\u201013\u2010185"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.12659\/msm.913514"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2012.180"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.335"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11183"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523\u2010020\u201000704\u20102"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9484"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201028648\u20103"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/mto.2016.18"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2015.1026511"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010014\u20100991\u20102"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201011\u20101157"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1408440"},{"key":"e_1_2_9_62_1","doi-asserted-by":"crossref","unstructured":"MerinoM KasamonY LiH et\u00a0al.FDA Approval Summary: Crizotinib for Pediatric and Young Adult Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma;2022.e29602.","DOI":"10.1002\/pbc.29602"},{"key":"e_1_2_9_63_1","volume-title":"FDA Approves Crizotinib for ALK\u2010Positive Inflammatory Myofibroblastic Tumor","year":"2022"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12128"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105919"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.mct\u201013\u20100242"}],"container-title":["Hematological Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hon.3194","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T08:21:16Z","timestamp":1703492476000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/hon.3194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,10]]},"references-count":65,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1002\/hon.3194"],"URL":"https:\/\/doi.org\/10.1002\/hon.3194","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/HON.3194\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.3194\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.3194\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.3194\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/HON.3194\/v2\/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":[[2023,6,10]]},"assertion":[{"value":"2023-01-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}