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Targeting the GCK pathway: a novel and selective therapeutic strategy against RAS-mutated multiple myeloma
Shirong Li1, Jing Fu1, Jun Yang1
1Department of Medicine and.
Abstract:
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 (KD) 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 a short hairpin RNA (shRNA)-resistant GCK, thereby excluding the potential off-target effects of GCK KD. In contrast, overexpression of shRNA-resistant GCK kinase-dead mutant (K45A) inhibited MM cell proliferation and failed to rescue the effects of GCK KD on MM growth inhibition, indicating that GCK kinase activity is critical for regulating MM cell proliferation and survival. Importantly, the higher sensitivity to GCK KD in RASMut cells suggests that targeting GCK is effective in MM, which harbors RAS mutations. In accordance with the effects of GCK KD, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 and led to MM cell proliferation inhibition accompanied by induction of apoptosis. Here, 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 immunomodulatory drug resistance in MM.
Insights
Targeting germinal center kinase (GCK) shows promise for treating multiple myeloma (MM) with RAS mutations. Silencing GCK inhibits MM cell growth by blocking key signaling pathways, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Multiple myeloma (MM) frequently harbors RAS mutations (NRAS, KRAS, BRAF) in up to 50% of patients.
- These mutations lead to constitutive protein activation, driving disease progression and potential drug resistance.
Purpose of the Study:
- To identify novel therapeutic targets in RAS-mutated MM.
- To investigate the role of germinal center kinase (GCK) in MM pathogenesis and its potential as a therapeutic target.
Main Methods:
- Germinal center kinase (GCK) knockdown (KD) in MM cell lines and in vivo models.
- Analysis of downstream signaling pathways, including MKK4/7-JNK phosphorylation.
- Assessment of key protein degradation (IKZF1/3, BCL-6, c-MYC).
- Rescue experiments using short hairpin RNA (shRNA)-resistant GCK and kinase-dead mutants.
- Treatment with a GCK inhibitor (TL4-12) in RAS-mutated MM cells.
Main Results:
- GCK KD inhibited MM cell proliferation and survival both in vitro and in vivo.
- GCK KD blocked MKK4/7-JNK phosphorylation and impaired degradation of IKZF1/3, BCL-6, and c-MYC.
- Overexpression of shRNA-resistant GCK rescued the inhibitory effects, while the kinase-dead mutant failed to rescue, confirming GCK's kinase activity is critical.
- RAS-mutated MM cells showed higher sensitivity to GCK KD.
- GCK inhibition with TL4-12 downregulated IKZF1 and BCL-6, inhibited proliferation, and induced apoptosis.
Conclusions:
- Germinal center kinase (GCK) is a novel and effective therapeutic target in RAS-mutated multiple myeloma.
- Targeting GCK kinase activity offers a potential strategy to overcome drug resistance in MM.
- GCK inhibitors may provide an alternative therapeutic approach for patients with immunomodulatory drug resistance.
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