TLK1 as a therapeutic target in TMZ resistant glioblastoma using small molecule inhibitor

Abstract

The acquired resistance to existing therapies poses a grave concern in achieving successful therapeutic outcomes. Temozolomide (TMZ), a widely used alkylating chemotherapeutic in Glioblastoma therapy, often encounters resistance, necessitating the investigation of the underlying mechanisms of TMZ-acquired resistance. To study TMZ resistance, a cell-based model system was generated by intermittently exposing glioblastoma cells to increasing concentrations and time of TMZ over six months. The survival response of cells at higher concentrations confirmed TMZ-resistant cells, which exhibited a phenotypic shift toward a mesenchymal-like state, with decreased epithelial traits, indicating mesenchymal-epithelial transition (MET). This transition likely facilitates the stabilization and clonal growth of TMZ-resistant cells. Subsequent analysis revealed elevated expression of TLK1, a DNA repair protein, thus reinforcing its potential involvement in mechanisms associated with acquired resistance. To explore the therapeutic aspect of TLK1 inhibition, we utilized an in-house developed TLK1 inhibitor, J54. The inhibition of TLK1 in TMZ-resistant cells enhanced cytotoxicity, indicating TLK1 as a potential target to combat TMZ resistance. Moreover, TLK1 inhibition reduced cell migration and invasion, implying its role in promoting metastasis. In conclusion, our study sheds light on the role of TLK1 in the context of TMZ resistance, highlighting its potential as a valuable target for therapeutic intervention.