ERK1/2 pro-survival signalling is suppressed by pirtobrutinib in ibrutinib-resistant MYD88-mutated lymphoma cells Journal Article
| Authors: | Munshi, M.; Liu, X.; Kofides, A.; Tsakmaklis, N.; Hunter, Z. R.; Guerrera, M. L.; Canning, A.; Gustine, J. N.; Liu, S.; Hatcher, J. M.; Chen, J.; Meid, K.; Sarosiek, S.; Flynn, C. A.; Branagan, A. R.; von Keudell, G.; Palomba, L. M.; Castillo, J. J.; Yang, G.; Treon, S. P. |
| Article Title: | ERK1/2 pro-survival signalling is suppressed by pirtobrutinib in ibrutinib-resistant MYD88-mutated lymphoma cells |
| Abstract: | Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88Mut) 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. BTKCys481 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 (BTKWT) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTKCys481 sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88Mut lymphoma cells expressing mutated BTKCys481. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88Mut lymphomas carrying BTKCys481 mutations. © 2024 British Society for Haematology and John Wiley & Sons Ltd. |
| Keywords: | genetics; mutation; metabolism; cell survival; map kinase signaling system; protein kinase inhibitor; waldenstroem macroglobulinemia; drug effect; drug resistance; drug resistance, neoplasm; cell line, tumor; pyrimidines; protein kinase inhibitors; pyrazole derivative; pyrazoles; tumor cell line; piperidines; drug therapy; pyrimidine derivative; myeloid differentiation factor 88; adenine; piperidine derivative; mapk signaling; bruton tyrosine kinase; waldenstrom macroglobulinemia; myd88; ibrutinib; humans; human; btk; agammaglobulinaemia tyrosine kinase; myd88 protein, human; erk1/2; pirtobrutinib; btk protein, human; abc dlbcl; waldenstrom's macroglobulinaemia |
| Journal Title: | British Journal of Haematology |
| Volume: | 205 |
| Issue: | 5 |
| ISSN: | 0007-1048 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2024-11-01 |
| Start Page: | 1866 |
| End Page: | 1872 |
| Language: | English |
| DOI: | 10.1111/bjh.19756 |
| PUBMED: | 39295138 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
