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ERK1/2 pro-survival signalling is suppressed by pirtobrutinib in ibrutinib-resistant MYD88-mutated lymphoma cells.

M MunshiX LiuA KofidesN TsakmaklisZachary R HunterM L GuerreraA CanningJ N GustineS LiuJ M HatcherJ ChenK MeidShayna R SarosiekC A FlynnA R BranaganG von KeudellL M PalombaJorge J CastilloG YangSteven P Treon
Published in: British journal of haematology (2024)
Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88 Mut ) 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 Cys481 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 WT ) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTK Cys481 sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88 Mut lymphoma cells expressing mutated BTK Cys481 . Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88 Mut lymphomas carrying BTK Cys481 mutations.
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