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 (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. [ABSTRACT FROM AUTHOR]