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

This is the authors' abstract. We don't add key points for this paper.

Summary 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.