TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma

Abstract

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.

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

“…BAY-1217389 and CFI-402257 significantly inhibited GBM cells colony formation. BAY-1217389 and CFI-402257 in combination with TMZ showed a higher cell viability decrease in both U251 and U87 cells than TMZ alone [173].…”

“…Different concentrations of BAY-1217389 and CFI-402257 showed a significant growth suppression effect on both U87 and U251 GBM cells in a dose dependent manner [173]. BAY-1217389 and CFI-402257 significantly inhibited GBM cells colony formation.…”

“…BAY-1217389 and CFI-402257 BAY-1217389 34 (Figure 9) is a selective TTK inhibitor, competitively binding its ATP site (IC 50 = 0.63 nM) [172]. It is characterized by a favorable PK profile, a high distribution volume and low blood clearance [173].…”

Integrated multi-omics analyses and functional validation reveal TTK as a novel EMT activator for endometrial cancer

“…A TTK-targeting small drug (compound 13) dramatically suppressed breast cancer development in nude mice [ 63 ]. According to some research, combining TTK inhibitors with chemotherapeutic drugs may significantly boost the effectiveness of destroying tumor cells [ 64 ]. BAY-1217389 and CFI-402257, two selective TTK inhibitors, greatly decreased glioblastoma multiforme cell proliferation and enhanced the growth-suppressive efficacy of temozolomide [ 64 ].…”

“…According to some research, combining TTK inhibitors with chemotherapeutic drugs may significantly boost the effectiveness of destroying tumor cells [ 64 ]. BAY-1217389 and CFI-402257, two selective TTK inhibitors, greatly decreased glioblastoma multiforme cell proliferation and enhanced the growth-suppressive efficacy of temozolomide [ 64 ]. Moreover, Mps1-IN-3, a selective small molecule TTK inhibitor, produced mitotic aberrations in glioblastoma cells, and its combination with vincristine increased cell death [ 65 ].…”