ERK1/2 pro‐survival signalling is suppressed by pirtobrutinib in ibrutinib‐resistant <i>MYD88</i>‐mutated lymphoma cells
Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88<sup>Mut</sup>) Waldenstrom's macroglobulinaemia and suppress nuclear factor kappa-light-chain-enhancer of activated B cells and extracellular signal-regulated kinases-1/2 (ERK1/2)-related signalling. BTK<sup>Cys481</sup> mutations are associated with cBTK-i acquired resistance and are accompanied by reactivation of ERK1/2 that promotes inflammatory cytokine secretion and paracrine-mediated resistance of BTK wild-type (BTK<sup>WT</sup>) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTK<sup>Cys481</sup> sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88<sup>Mut</sup> lymphoma cells expressing mutated BTK<sup>Cys481</sup>. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88<sup>Mut</sup> lymphomas carrying BTK<sup>Cys481</sup> mutations.
Authors
- Aoife Canning (ORCID: https://orcid.org/0000-0002-0515-7889)
- John M. Hatcher (ORCID: https://orcid.org/0000-0002-3540-7842)
- Jorge J. Castillo (ORCID: https://orcid.org/0000-0001-9490-7532)
- G. von Keudell
- Lia Palomba
- Zachary R. Hunter (ORCID: https://orcid.org/0000-0002-1689-1691)
- Andrew R. Branagan (ORCID: https://orcid.org/0000-0002-3868-9267)
- Amanda Kofides
- Xia Liu (ORCID: https://orcid.org/0000-0002-3110-9602)
- Catherine Flynn (ORCID: https://orcid.org/0000-0001-7645-3469)
- Maria Luisa Guerrera (ORCID: https://orcid.org/0000-0002-0730-4678)
- Nickolas Tsakmaklis
- Manit Munshi
- Joshua N. Gustine (ORCID: https://orcid.org/0000-0001-6717-7669)
- Shayna Sarosiek (ORCID: https://orcid.org/0000-0002-0075-6735)
- Kirsten Meid
- Steven P. Treon (ORCID: https://orcid.org/0000-0001-6393-6154)
- Guang Yang (ORCID: https://orcid.org/0000-0003-3049-4200)
- Jie Chen (ORCID: https://orcid.org/0000-0002-1678-3586)
- Shirong Liu (ORCID: https://orcid.org/0000-0002-3821-9134)
Institutions
- Boston University (US)
- Boston Medical Center (US)
- Beth Israel Deaconess Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- University Medical Center (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- British Journal of Haematology
- Published
- 2024-09-18
- DOI
- https://doi.org/10.1111/bjh.19756
- Citations
- 3
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.31
Funders
- International Waldenstrom's Macroglobulinemia Foundation
- Leukemia and Lymphoma Society