BACKGROUND: Despite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired BTK or PLCγ2 mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario. METHODS: We established a novel patient-derived ibrutinib-resistant mantle cell lymphoma (MCL) line named MCIR1. Using immunological, molecular, and cytogenetic approaches, we comprehensively characterized MCIR1 and further demonstrated its utility in the study of resistance mechanisms and treatments to overcome this resistance. RESULTS: We show that MCIR1 is a bona fide ibrutinib-resistant MCL cell line with normal BTK-/PLCγ2 but ibrutinib-resistant ERK1/2 and AKT1 signaling. RNA-Seq analysis revealed a robust non-canonical NF-kB signaling that drives the ibrutinib resistance. We also demonstrate the potential utility of a MCIR1-based cell and mouse model for the discovery of new treatments to overcome BTK inhibitor resistance. CONCLUSIONS: We have established the first patient-derived ibrutinib-resistant MCL cell line MCIR1 that lacks BTK or PLCγ2 mutations but exhibits a hyperactive non-canonical NF-kB pathway. We further demonstrate its utility in the discovery and validation of new drugs to overcome this resistance.
BACKGROUND: Despite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired BTK or PLCγ2 mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario. METHODS: We established a novel patient-derived ibrutinib-resistant mantle cell lymphoma (MCL) line named MCIR1. Using immunological, molecular, and cytogenetic approaches, we comprehensively characterized MCIR1 and further demonstrated its utility in the study of resistance mechanisms and treatments to overcome this resistance. RESULTS: We show that MCIR1 is a bona fide ibrutinib-resistant MCL cell line with normal BTK-/PLCγ2 but ibrutinib-resistant ERK1/2 and AKT1 signaling. RNA-Seq analysis revealed a robust non-canonical NF-kB signaling that drives the ibrutinib resistance. We also demonstrate the potential utility of a MCIR1-based cell and mouse model for the discovery of new treatments to overcome BTK inhibitor resistance. CONCLUSIONS: We have established the first patient-derived ibrutinib-resistant MCL cell line MCIR1 that lacks BTK or PLCγ2 mutations but exhibits a hyperactive non-canonical NF-kB pathway. We further demonstrate its utility in the discovery and validation of new drugs to overcome this resistance.
Authors: Andrew W Roberts; Shuo Ma; Thomas J Kipps; Steven E Coutre; Matthew S Davids; Barbara Eichhorst; Michael Hallek; John C Byrd; Kathryn Humphrey; Lang Zhou; Brenda Chyla; Jacqueline Nielsen; Jalaja Potluri; Su Young Kim; Maria Verdugo; Stephan Stilgenbauer; William G Wierda; John F Seymour Journal: Blood Date: 2019-04-25 Impact factor: 22.113
Authors: Jeffrey A Jones; Anthony R Mato; William G Wierda; Matthew S Davids; Michael Choi; Bruce D Cheson; Richard R Furman; Nicole Lamanna; Paul M Barr; Lang Zhou; Brenda Chyla; Ahmed Hamed Salem; Maria Verdugo; Rod A Humerickhouse; Jalaja Potluri; Steven Coutre; Jennifer Woyach; John C Byrd Journal: Lancet Oncol Date: 2017-12-12 Impact factor: 41.316
Authors: John C Byrd; Richard R Furman; Steven E Coutre; Ian W Flinn; Jan A Burger; Kristie A Blum; Barbara Grant; Jeff P Sharman; Morton Coleman; William G Wierda; Jeffrey A Jones; Weiqiang Zhao; Nyla A Heerema; Amy J Johnson; Juthamas Sukbuntherng; Betty Y Chang; Fong Clow; Eric Hedrick; Joseph J Buggy; Danelle F James; Susan O'Brien Journal: N Engl J Med Date: 2013-06-19 Impact factor: 91.245
Authors: Xiaohong Zhao; Tint Lwin; Ariosto Silva; Bijal Shah; Jiangchuan Tao; Bin Fang; Liang Zhang; Kai Fu; Chengfeng Bi; Jiannong Li; Huijuan Jiang; Mark B Meads; Timothy Jacobson; Maria Silva; Allison Distler; Lancia Darville; Ling Zhang; Ying Han; Dmitri Rebatchouk; Maurizio Di Liberto; Lynn C Moscinski; John M Koomen; William S Dalton; Kenneth H Shain; Michael Wang; Eduardo Sotomayor; Jianguo Tao Journal: Nat Commun Date: 2017-04-18 Impact factor: 14.919