Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies

Abstract

In most cell types, nuclear beta-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of beta-catenin but critically depended on GSK3B for effective beta-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that beta-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, beta-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive beta-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3B small molecule inhibitors to subvert beta-catenin degradation. Clinically approved GSK3B-inhibitors that achieved favorable safety profiles at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of beta-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3B-inhibitors for targeted engagement of lymphoid-specific beta-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory B-cell malignancies. HIGHLIGHTS Unlike other cell lineages, B-cells express nuclear beta-catenin protein at low baseline levels and depend on GSK3B for its degradation. In B-cells, beta-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. CRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed beta-catenin-dependent Myc repression and induction of cell death. The discovery of GSK3B-dependent degradation of beta-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3B-inhibitors for the treatment of refractory B-cell malignancies.

Elraglusib induces cytotoxicity via direct microtubule destabilisation independently of GSK3 inhibition

“…We also showed that other validated small molecule GSK3α/β inhibitors do not share the anti-lymphoma properties of elraglusib and that GSK3A/B shRNA knockdown did not affect the elraglusib IC50 (17,18). Preprint data from Cosgun et al also reports broad cytotoxic effects of elraglusib in the absence of β-catenin or myc stabilisation suggesting it occurs without significant GSK3 inhibition (17,26). Together, these findings question the requirement for GSK3 inhibition in the mechanism of action of elraglusib.…”