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Pirtobrutinib targe...
Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance
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- Naeem, Aishath (författare)
- Massachusetts Institute of Technology,Harvard Medical School
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- Utro, Filippo (författare)
- IBM Research
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- Wang, Qing (författare)
- Karolinska Institutet
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- Cha, Justin (författare)
- Massachusetts Institute of Technology
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- Vihinen, Mauno (författare)
- Lund University,Lunds universitet,Proteinbioinformatik,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Protein Bioinformatics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Martindale, Stephen (författare)
- Harvard Medical School
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- Zhou, Yinglu (författare)
- Harvard University
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- Ren, Yue (författare)
- Harvard University
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- Tyekucheva, Svitlana (författare)
- Harvard University
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- Kim, Annette S. (författare)
- Brigham and Women's Hospital / Harvard Medical School
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- Fernandes, Stacey M. (författare)
- Harvard Medical School
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- Saksena, Gordon (författare)
- Massachusetts Institute of Technology
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- Rhrissorrakrai, Kahn (författare)
- IBM Research
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- Levovitz, Chaya (författare)
- IBM Research
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- Danysh, Brian P. (författare)
- Massachusetts Institute of Technology
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- Slowik, Kara (författare)
- Massachusetts Institute of Technology
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- Jacobs, Raquel A. (författare)
- Massachusetts Institute of Technology
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- Davids, Matthew S. (författare)
- Brigham and Women's Hospital / Harvard Medical School,Harvard Medical School
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- Lederer, James A. (författare)
- Brigham and Women's Hospital / Harvard Medical School
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- Zain, Rula (författare)
- Karolinska Institutet
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- Smith, C. I.Edvard (författare)
- Karolinska Institutet
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- Leshchiner, Ignaty (författare)
- Massachusetts Institute of Technology
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- Parida, Laxmi (författare)
- IBM Research
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- Getz, Gad (författare)
- Massachusetts Institute of Technology,Massachusetts General Hospital,Harvard Medical School
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- Brown, Jennifer R. (författare)
- Massachusetts Institute of Technology,Harvard Medical School,Brigham and Women's Hospital / Harvard Medical School
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(creator_code:org_t)
- 2022-10-26
- 2023
- Engelska 15 s.
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:9, s. 1929-1943
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
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- Av författaren/redakt...
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Naeem, Aishath
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Utro, Filippo
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Wang, Qing
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Cha, Justin
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Vihinen, Mauno
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Martindale, Step ...
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visa fler...
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Zhou, Yinglu
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Ren, Yue
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Tyekucheva, Svit ...
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Kim, Annette S.
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Fernandes, Stace ...
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Saksena, Gordon
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Rhrissorrakrai, ...
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Levovitz, Chaya
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Danysh, Brian P.
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Slowik, Kara
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Jacobs, Raquel A ...
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Davids, Matthew ...
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Lederer, James A ...
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Zain, Rula
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Smith, C. I.Edva ...
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Leshchiner, Igna ...
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Parida, Laxmi
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Getz, Gad
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Brown, Jennifer ...
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Hematologi
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Blood Advances
- Av lärosätet
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Lunds universitet
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Karolinska Institutet