Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors

In nine patients with chronic lymphocytic leukemia that responded to the noncovalent BTK inhibitor pirtobrutinib and then developed resistance, analysis revealed a number of new mutations in the BTK kinase domain and occasional mutations in downstream PLCγ2. Despite the inactivity of BTK, alternativ...

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Bibliographic Details
Published in:	The New England journal of medicine Vol. 386; no. 8; pp. 735 - 743
Main Authors:	Wang, Eric, Mi, Xiaoli, Thompson, Meghan C, Montoya, Skye, Notti, Ryan Q, Afaghani, Jumana, Durham, Benjamin H, Penson, Alex, Witkowski, Matthew T, Lu, Sydney X, Bourcier, Jessie, Hogg, Simon J, Erickson, Caroline, Cui, Dan, Cho, Hana, Singer, Michael, Totiger, Tulasigeri M, Chaudhry, Sana, Geyer, Mark, Alencar, Alvaro, Linley, Adam J, Palomba, M. Lia, Coombs, Catherine C, Park, Jae H, Zelenetz, Andrew, Roeker, Lindsey, Rosendahl, Mary, Tsai, Donald E, Ebata, Kevin, Brandhuber, Barbara, Hyman, David M, Aifantis, Iannis, Mato, Anthony, Taylor, Justin, Abdel-Wahab, Omar
Format:	Journal Article
Language:	English
Published:	United States Massachusetts Medical Society 24.02.2022
Subjects:	Adenine - analogs & derivatives Adenine - pharmacology Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors Agammaglobulinaemia Tyrosine Kinase - genetics Agammaglobulinaemia Tyrosine Kinase - ultrastructure Biopsy Bruton's tyrosine kinase Cancer Cell activation Chronic lymphocytic leukemia Drug dosages Drug Resistance, Neoplasm - genetics Genomic analysis Hematology Humans Kinases Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Lymphatic leukemia Lymphocytes B Lymphoma Middle Aged Mutation Oncology Patients Phospholipase C Phospholipase C gamma - genetics Piperidines - pharmacology Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proteins Receptors, Antigen, B-Cell - metabolism Sequence Analysis, RNA Signal Transduction - drug effects Transcription activation Treatments in Oncology Tyrosine kinase inhibitors
ISSN:	0028-4793, 1533-4406, 1533-4406
Online Access:	Get full text
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Summary:	In nine patients with chronic lymphocytic leukemia that responded to the noncovalent BTK inhibitor pirtobrutinib and then developed resistance, analysis revealed a number of new mutations in the BTK kinase domain and occasional mutations in downstream PLCγ2. Despite the inactivity of BTK, alternative pathways of B-cell–receptor signaling were evident.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Drs. Wang, Mi, Thompson, Mato, Taylor, and Abdel-Wahab contributed equally to this article.
ISSN:	0028-4793 1533-4406 1533-4406
DOI:	10.1056/NEJMoa2114110