Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.
Ibrutinib (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.
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Shruti
S
Sharma
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Natalie
N
Galanina
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Ailin
A
Guo
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Jimmy
J
Lee
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.|Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA.
Sabah
S
Kadri
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Charles
C
Van Slambrouck
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Bradley
B
Long
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Weige
W
Wang
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Mei
M
Ming
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Larissa V
LV
Furtado
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Jeremy P
JP
Segal
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Wendy
W
Stock
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Girish
G
Venkataraman
Ben-May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
Wei-Jen
WJ
Tang
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Pin
P
Lu
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Yue Lynn
YL
Wang
D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D018909:src Homology Domains
D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine
BTK; Richter transformation; chronic lymphocytic leukemia; ibrutinib resistance; molecular targeted therapy