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Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance

Naeem, Aishath ; Utro, Filippo ; Wang, Qing ; Cha, Justin ; Vihinen, Mauno LU orcid ; Martindale, Stephen ; Zhou, Yinglu ; Ren, Yue ; Tyekucheva, Svitlana and Kim, Annette S. , et al. (2023) In Blood Advances 7(9). p.1929-1943
Abstract

Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor... (More)

Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
7
issue
9
pages
15 pages
publisher
American Society of Hematology
external identifiers
  • pmid:36287227
  • scopus:85162853942
ISSN
2473-9529
DOI
10.1182/bloodadvances.2022008447
language
English
LU publication?
yes
id
9e3e3d94-2eb7-4297-acf5-a426d5d530d2
date added to LUP
2023-09-21 11:17:29
date last changed
2024-04-19 02:32:10
@article{9e3e3d94-2eb7-4297-acf5-a426d5d530d2,
  abstract     = {{<p>Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.</p>}},
  author       = {{Naeem, Aishath and Utro, Filippo and Wang, Qing and Cha, Justin and Vihinen, Mauno and Martindale, Stephen and Zhou, Yinglu and Ren, Yue and Tyekucheva, Svitlana and Kim, Annette S. and Fernandes, Stacey M. and Saksena, Gordon and Rhrissorrakrai, Kahn and Levovitz, Chaya and Danysh, Brian P. and Slowik, Kara and Jacobs, Raquel A. and Davids, Matthew S. and Lederer, James A. and Zain, Rula and Smith, C. I.Edvard and Leshchiner, Ignaty and Parida, Laxmi and Getz, Gad and Brown, Jennifer R.}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1929--1943}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2022008447}},
  doi          = {{10.1182/bloodadvances.2022008447}},
  volume       = {{7}},
  year         = {{2023}},
}