Research Papers:

Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL

Shruti Sharma, Natalie Galanina, Ailin Guo, Jimmy Lee, Sabah Kadri, Charles Van Slambrouck, Bradley Long, Weige Wang, Mei Ming, Larissa V. Furtado, Jeremy P. Segal, Wendy Stock, Girish Venkataraman, Wei-Jen Tang, Pin Lu and Yue Lynn Wang _

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Oncotarget. 2016; 7:68833-68841. https://doi.org/10.18632/oncotarget.11932

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Shruti Sharma1,*, Natalie Galanina2,*, Ailin Guo1,*, Jimmy Lee1, Sabah Kadri1,3, Charles Van Slambrouck1, Bradley Long1, Weige Wang1, Mei Ming1, Larissa V. Furtado1, Jeremy P. Segal1, Wendy Stock2, Girish Venkataraman1, Wei-Jen Tang4, Pin Lu1, Yue Lynn Wang1

1Department of Pathology, University of Chicago, Chicago, IL 60637, USA

2Department of Medicine, University of Chicago, Chicago, IL 60637, USA

3Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA

4Ben-May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA

*These authors have contributed equally to this work

Correspondence to:

Yue Lynn Wang, email: [email protected]

Keywords: chronic lymphocytic leukemia, Richter transformation, ibrutinib resistance, BTK, molecular targeted therapy

Received: June 04, 2016    Accepted: August 15, 2016    Published: September 10, 2016


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.

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