Epigenetic Rewiring of BCR Signaling as a Novel Mechanism of Ibrutinib Resistance in ABC-DLBCL

In this issue of Blood Cancer Discovery, Schaffer and colleagues uncover a novel epigenetic mechanism of resistance to the Bruton tyrosine kinase inhibitor ibrutinib in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), whereby tumor cells rewire the B-cell receptor (BCR)-driven NF-kappa B signaling cascade through the small GTPase RAC2. This circuit can be efficiently targeted by RAC1/2 small-molecule inhibitors, suggesting a promising new therapeutic approach to overcome acquired ibrutinib resistance in ABC-DLBCL and possibly other B-cell malignancies relying on active BCR signaling.