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

Naeem, Aishath (author)
Harvard Medical School,Massachusetts Institute of Technology
Utro, Filippo (author)
IBM Research
Wang, Qing (author)
Karolinska Institutet
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Cha, Justin (author)
Massachusetts Institute of Technology
Vihinen, Mauno (author)
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
Martindale, Stephen (author)
Harvard Medical School
Zhou, Yinglu (author)
Harvard University
Ren, Yue (author)
Harvard University
Tyekucheva, Svitlana (author)
Harvard University
Kim, Annette S. (author)
Brigham and Women's Hospital / Harvard Medical School
Fernandes, Stacey M. (author)
Harvard Medical School
Saksena, Gordon (author)
Massachusetts Institute of Technology
Rhrissorrakrai, Kahn (author)
IBM Research
Levovitz, Chaya (author)
IBM Research
Danysh, Brian P. (author)
Massachusetts Institute of Technology
Slowik, Kara (author)
Massachusetts Institute of Technology
Jacobs, Raquel A. (author)
Massachusetts Institute of Technology
Davids, Matthew S. (author)
Brigham and Women's Hospital / Harvard Medical School,Harvard Medical School
Lederer, James A. (author)
Brigham and Women's Hospital / Harvard Medical School
Zain, Rula (author)
Karolinska Institutet
Smith, C. I.Edvard (author)
Karolinska Institutet
Leshchiner, Ignaty (author)
Massachusetts Institute of Technology
Parida, Laxmi (author)
IBM Research
Getz, Gad (author)
Massachusetts General Hospital,Massachusetts Institute of Technology,Harvard Medical School
Brown, Jennifer R. (author)
Brigham and Women's Hospital / Harvard Medical School,Massachusetts Institute of Technology,Harvard Medical School
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 (creator_code:org_t)
2022-10-26
2023
English 15 s.
In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:9, s. 1929-1943
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

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