GCK Inhibition Enhances Iberdomide Anti-Myeloma Effects by Promoting IKZF1 Degradation via a CRBN-Independent Mechanism Open Access

• GCK inhibition induces IKZF1 degradation through a CRBN-independent mechanism in multiple myeloma.

• GCK inhibition effectively overcomes IMiDs resistance in MM and synergistically enhances the anti-MM effects of the CELMoD: iberdomide.

Our recent study identifies germline center kinase GCK as a novel therapeutic target in RAS mutated (RAS^Mut) multiple myeloma (MM). Inhibiting GCK downregulates critical transcriptional factors, notably IKZF1/3, BCL-6, and c-MYC proteins, leading to MM cell growth inhibition and cell death. Distinct from IMiDs-induced IKZF1/3 degradation, GCK inhibition triggers IKZF1/3 proteolysis through a CRBN E3 ligase-independent mechanism. Here we demonstrated that GCK inhibition overcomes IMiDs resistance in MM. An isogenic subline of MM.1S cells with acquired lenalidomide resistance remains sensitive to GCK inhibition-induced IKZF1/3 downregulation and cell growth inhibition. Consistently, the CRBN-resistant IKZF1 Q146H mutant maintains sensitivity to GCK inhibitor-induced degradation as the IKZF1 wildtype protein, suggesting a CRBN-independent protein degradation. In accordance with the distinct IKZF1/3 degradation mechanisms, GCK silencing enhances iberdomide-induced IKZF1/3 and c-MYC downregulation and MM growth inhibition. More importantly, the combination of GCK inhibitor with iberdomide exhibited synergistic anti-MM effects on a panel of MM cell lines and primary plasma cells. The synergistic effects were confirmed in the MM xenograft mouse model with combining GCK silencing and iberdomide resulting in significantly enhanced tumor inhibition and prolonged mice survival compared to single treatments. These findings underscore GCK as a promising therapeutic target for bypassing IMiDs resistance in MM. Combining GCK inhibition with iberdomide could provide a novel strategy to manage relapsed or refractory patients with multi-drug resistance especially after the exhaustion of immunotherapy.