Sharma SGalanina NGuo ALee JKadri SVan Slambrouck CLong BWang WMing MFurtado L.VSegal J.PStock WVenkataraman GTang W.-JLu PWang Y.L.LI-HSING LEE2022-11-112022-11-11201619492553https://www.scopus.com/inward/record.uri?eid=2-s2.0-85010757834&doi=10.18632%2fONCOTARGET.11932&partnerID=40&md5=145c4871688521ce3f9f25fd9c4e77e8https://scholars.lib.ntu.edu.tw/handle/123456789/624851Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient's clinical course identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTKT316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S. Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients. © 2015. Oncotarget.BTK; Chronic lymphocytic leukemia; Ibrutinib resistance; Molecular targeted therapy; Richter transformationBruton tyrosine kinase; cyclophosphamide; fludarabine; ibrutinib; obinutuzumab; rituximab; Agammaglobulinaemia tyrosine kinase; antineoplastic agent; ibrutinib; protein kinase inhibitor; protein tyrosine kinase; pyrazole derivative; pyrimidine derivative; adult; Article; BTK gene; cancer growth; cancer patient; case report; chronic lymphatic leukemia; clinical article; disease course; drug treatment failure; female; gene identification; gene mutation; human; human cell; human tissue; leukemia relapse; middle aged; protein domain; cell transformation; chronic lymphatic leukemia; dna mutational analysis; drug resistance; genetics; high throughput sequencing; mutation; Src homology domain; tumor recurrence; Antineoplastic Agents; Cell Transformation, Neoplastic; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; src Homology Domainsjournal article10.18632/ONCOTARGET.11932276266982-s2.0-85010757834