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

Abstract

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-κB 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.See related article by Shaffer et al., p. 630.

Figure 1.

Modes of ibrutinib resistance in ABC/MCD-DLBCL. Simplified schematic of the chronic active BCR signaling pathway leading to constitutive NF-κB activation in ABC-DLBCL of the MCD genetic subgroup. Positive and negative pathway regulators commonly targeted by genetic mutations are color-coded in orange (CD79α/β) and magenta (CARD11, TNFAIP3, and MYD88). A double oval is used to illustrate the downstream activation of the NF-κB complex. The My–T–BCR supercomplex (MYD88–TLR9–BCR) is also indicated. In sensitive cells, BTK inhibition by ibrutinib blocks proliferation and survival (left). The mechanism of epigenetic ibrutinib resistance described by Shaffer and colleagues is illustrated in the middle, where increased amounts of RAC2 and enhanced RAC2–PLCγ2 interaction substitute for BTK in rewiring BCR signaling to downstream NF-κB. This phenotypic shift is driven by TCF4-dependent enhancer activation of critical target genes (only RAC2 and TLR9 shown). On the right, genetic mutations blocking the covalent binding of ibrutinib to BTK or activating PLCγ2 (red thunderbolts) lead to irreversible ibrutinb resistance. BTK, Bruton tyrosine kinase; RAC2i, RAC2 inhibitor.