| RRC ID |
71768
|
| 著者 |
Dhami K, Chakraborty A, Gururaja TL, Cheung LW, Sun C, DeAnda F, Huang X.
|
| タイトル |
Kinase-deficient BTK mutants confer ibrutinib resistance through activation of the kinase HCK.
|
| ジャーナル |
Sci Signal
|
| Abstract |
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib irreversibly binds BTK at Cys481, inhibiting its kinase activity and thus blocking transduction of B cell receptor (BCR) signaling. Although ibrutinib is durably effective in patients with B cell malignancies, many patients still develop ibrutinib-resistant disease. Resistance can arise because of mutations at the ibrutinib-binding site in BTK. Here, we characterized the mechanism by which two BTK mutations, C481F and C481Y, may lead to ibrutinib resistance. Both mutants lacked detectable kinase activity in in vitro kinase assays. Structural modeling suggested that bulky Phe and Tyr side chains at position 481 sterically hinder access to the ATP-binding pocket in BTK, contributing to loss of kinase activity. Nonetheless, BCR signaling still propagated through BTK C481F and C481Y mutants to downstream effectors, the phospholipase PLCγ2 and the transcription factor NF-κB. This maintenance of BCR signaling was partially achieved through the physical recruitment and kinase-independent activation of hematopoietic cell kinase (HCK). Upon BCR activation, BTK C481F or C481Y was phosphorylated by Src family kinases at Tyr551, which then bound to the SH2 domain of HCK. Modeling suggested that this binding disrupted an intramolecular autoinhibitory interaction in HCK. Activated HCK subsequently phosphorylated PLCγ2, which propagated BCR signaling and promoted clonogenic cell proliferation. This kinase-independent mechanism could inform therapeutic approaches to CLL bearing either the C481F or C481Y BTK mutants.
|
| 巻・号 |
15(736)
|
| ページ |
eabg5216
|
| 公開日 |
2022-5-31
|
| DOI |
10.1126/scisignal.abg5216
|
| PMID |
35639855
|
| MeSH |
Adenine / analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
Drug Resistance, Neoplasm
Humans
Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell* / genetics
Phospholipase C gamma / genetics
Piperidines* / pharmacology
Proto-Oncogene Proteins c-hck* / metabolism
|
| IF |
6.467
|
| リソース情報 |
| ヒト・動物細胞 |
DT40(RCB1464) |
