Key Points

  • GCK activity is critical in multiple myeloma harboring RAS mutations.

  • GCK inhibition induces degradation of IKZF1/3 in a CRBN-independent fashion.

In multiple myeloma (MM), frequent mutations of NRAS, KRAS, or BRAF are found in up to 50% of newly diagnosed patients. The majority of the NRAS, KRAS, and BRAF mutations occur in hotspots causing constitutive activation of the corresponding proteins. Thus targeting RAS mutation in MM will increase therapeutic efficiency and potentially overcome drug-resistance. We identified Germinal Center Kinase (GCK) as a novel therapeutic target in MM with RAS mutation. GCK knockdown in MM cells demonstrated in vitro and in vivo that silencing of GCK induces MM cell growth inhibition, associated with blocked MKK4/7-JNK phosphorylation and impaired degradation of IKZF1/3, BCL-6, and c-MYC. These effects were rescued by overexpression of an shRNA-resistant GCK, thereby excluding the potential off-target effects of GCK knockdown. In contrast, overexpression of shRNA-resistant GCK kinase-dead mutant (K45A) inhibited MM cell proliferation and failed to rescue the effects of GCK knockdown on MM growth inhibition, indicating that GCK kinase activity is critical for regulating MM cell proliferation and survival. Importantly, the higher sensitivity to GCK knockdown in RASMut cells suggests that targeting GCK is effective in multiple myeloma which harbors RAS mutations. In accordance with the effects of GCK knockdown, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 and led to MM cell proliferation inhibition accompanied by induction of apoptosis. Hereby our data identify GCK as a novel target in RASMut MM cells, providing a rationale to treat RAS mutations in MM. Furthermore, GCK inhibitors might represent an alternative therapy to overcome IMiD-resistance in MM.

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