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

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.