Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (27626698)
Authors Sharma S, Galanina N, Guo A, Lee J, Kadri S, Van Slambrouck C, Long B, Wang W, Ming M, Furtado LV, Segal JP, Stock W, Venkataraman G, Tang WJ, Lu P, Wang YL
Title Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 7 42 2016 Oct 18 68833-68841 Oncotarget
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BTK T316A missense unknown BTK T316A lies within the SH2 domain of the Btk protein (UniProt.org). T316A results in a partial increase in Btk autophosphorylation in an in vitro assay (PMID: 33226337), and confers resistance to Imbruvica (ibrutinib) in culture (PMID: 27626698), but has not been fully biochemically characterized, and therefore, its effect on Btk protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK T316A lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cells expressing BTK T316A were resistant to Imbruvica (ibrutinib) in culture (PMID: 27626698) 27626698
BTK C481S lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cells expressing BTK C481S were resistant to Imbruvica (ibrutinib) in culture (PMID: 27626698) 27626698