{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:13:35Z","timestamp":1791825215725,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,6,24]],"date-time":"2014-06-24T00:00:00Z","timestamp":1403568000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Start up funding from my institutions: U. of Chicago and Weill Cornell Medical College"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Ibrutinib inhibits <jats:styled-content style=\"fixed-case\">B<\/jats:styled-content>ruton tyrosine kinase (<jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content>), a key component of early B\u2010cell receptor (<jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content>) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed\/refractory mantle cell lymphoma (<jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content>) demonstrated a remarkable response rate. However, approximately one\u2010third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content> cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> activity than normal B cells and <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content> cells show differential sensitivity to <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> inhibition. Genetic knockdown of <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> inhibits the growth, survival and proliferation of ibrutinib\u2010sensitive but not resistant <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content> cell lines, suggesting that ibrutinib acts through <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> to produce its anti\u2010tumour activities. Interestingly, inhibition of <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 and <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>, but not <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> phosphorylation <jats:italic>per se<\/jats:italic>, correlates well with cellular response to <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to <jats:styled-content style=\"fixed-case\">BTK<\/jats:styled-content> inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.<\/jats:p>","DOI":"10.1111\/bjh.12974","type":"journal-article","created":{"date-parts":[[2014,6,24]],"date-time":"2014-06-24T13:13:08Z","timestamp":1403615588000},"page":"849-861","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Characterization of ibrutinib\u2010sensitive and \u2010resistant mantle lymphoma cells"],"prefix":"10.1111","volume":"166","author":[{"given":"Jiao","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhua","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Medicine Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morton","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Medicine Weill Cornell Medical College New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Lynn","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,6,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.42.7906"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M800515-MCP200"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/08830185.2012.664797"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2013.31.15_suppl.7014","article-title":"Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL)","volume":"31","author":"Chang B.Y.","year":"2013","journal-title":"Journal of Clinical Oncology"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-482125"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-333773"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.358"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041720"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2013.07.028"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2004.04.008"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12206"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08638"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-3152"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.7.1973"},{"key":"e_1_2_8_16_1","first-page":"4914","article-title":"A Novel BTK Mutation reactivates BCR signaling and confers acquired resistance of CLL to ibrutinib","volume":"122","author":"Furman R.R.","year":"2013","journal-title":"Blood (ASH Annual Meeting Abstract)"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1402716"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.11.012"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-343434"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-030409-101216"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1004594107"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311985200"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-02-003921"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2230"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.7.1297"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1589"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132541"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.304"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-012-0254-8"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200600221"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2011.09.008"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-189977"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-011-0019-7"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05883.x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1519"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306220"},{"key":"e_1_2_8_37_1","first-page":"686","article-title":"The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI\u201032765), has preferential activity in the ABC subtype of relapsed\/refractory de novo diffuse large B\u2010cell lymphoma (DLBCL): interim results of a multicenter, open\u2010label, phase 2 study","volume":"120","author":"Wilson W.H.","year":"2012","journal-title":"Blood (ASH Annual Meeting Abstracts)"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.163"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.05.024"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3937"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbjh.12974","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.12974","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T23:05:20Z","timestamp":1696287920000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.12974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,24]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2014,9]]}},"alternative-id":["10.1111\/bjh.12974"],"URL":"https:\/\/doi.org\/10.1111\/bjh.12974","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,24]]},"assertion":[{"value":"2014-02-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-05-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-06-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}