TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma

Background: Temozolomide (TMZ) resistance remains the main therapy challenge in patients with glioblastoma multiforme (GBM). TTK Protein Kinase (TTK) contributes to the radioresistance and chemoresistance in many malignancies. However, the role of TTK in the TMZ resistance of GBM cells remains unknown.

Methods: The expression of TTK was measured by western blot. The proliferation of GBM cells was assessed through MTT assay and clonogenic assay. Cell apoptosis was evaluated using western blot. LC3B puncta were detected using immunohistochemistry staining. The mouse xenograft model was used to investigate the role of TTK in vivo.

Results: Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.

Conclusions: We demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM.

 

Comments:

The study you described investigates the role of TTK Protein Kinase (TTK) in promoting resistance to Temozolomide (TMZ) in glioblastoma multiforme (GBM) cells. Here's a summary of the key findings and implications of the research:

### **Key Findings:**

1. **TTK Expression and TMZ Resistance:** The researchers found that TTK expression was associated with resistance to TMZ in GBM cells. Knocking down TTK increased the sensitivity of GBM cells to TMZ, while overexpression of TTK induced TMZ resistance.

2. **TTK Inhibitors:** Two specific TTK inhibitors, BAY-1217389 and CFI-402257, were used in the study. These inhibitors not only inhibited GBM cell proliferation on their own but also enhanced the growth-suppressive effect of TMZ.

3. **Autophagy Regulation:** TTK was found to regulate autophagy levels in GBM cells. Knockdown of TTK decreased autophagy, while overexpression of TTK promoted autophagy. Specific TTK inhibitors also suppressed the autophagy process in GBM cells.

4. **Autophagy and TMZ Resistance:** Autophagy was linked to TMZ resistance in GBM cells. Inhibition of autophagy using chloroquine (CQ) reversed the TMZ resistance function of TTK in GBM cells and in a mouse xenograft model.

### **Implications:**

1. **Targeted Therapy:** TTK inhibitors, when used in combination with TMZ, could potentially overcome TMZ resistance in GBM. These inhibitors not only directly inhibit TTK, but they also suppress autophagy, a process that contributes to TMZ resistance.

2. **Clinical Relevance:** The findings suggest a potential therapeutic strategy for GBM patients. Combining TTK inhibitors with standard TMZ treatment might enhance the efficacy of chemotherapy and improve patient outcomes.

3. **Future Research:** Further research could explore the specific mechanisms through which TTK induces autophagy in GBM cells. Understanding these mechanisms in detail could provide insights into novel therapeutic targets.

4. **Patient Stratification:** The study implies that patients with high TTK expression might benefit from TTK inhibitors in combination with TMZ. This indicates the importance of molecular profiling in patient stratification for personalized treatment approaches.

In summary, the research highlights TTK as a potential target for overcoming TMZ resistance in GBM. The study not only elucidates the role of TTK in promoting resistance but also provides a promising direction for future clinical interventions in GBM patients.

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S8215	BAY 1217389	BAY 1217389 is an orally bioavailable, selective inhibitor of the serine/threonine kinase monopolar spindle 1 (Mps1) with IC50 values below 10 nmol/L while showing an excellent selectivity profile.

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MPS1