TLK1 (Tousled Like Kinase 1)

Circ-MBOAT2 promotes NSCLC cell proliferation, EMT and immune escape by competitively binding to miR-664b-3p to promote TLK1 expression.

Temozolomide (TMZ), a widely used alkylating chemotherapeutic in Glioblastoma therapy, often encounters resistance, necessitating the investigation of the underlying mechanisms of TMZ-acquired 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.

To establish this, we used both pharmacologic and systemic approaches with genetically engineered mouse models and the use of IVIS. The results of targeting the TLK1>MK5 axis support the notion that this axis is essential for the spread of metastatic cells and the development of age-related metastases.

Additionally, the combination of anti-androgens and 5n reduces the clonogenicity of cells, causes an accumulation of DNA damage, and induces apoptosis cell death in the LNCaP cells. We anticipate that our step towards exploring a new class of potent TLK1 inhibitors would aid in elevating the therapeutics to existing prostate cancer therapy and provide strong validation for future drug design for more potent and specific TLK1 inhibitors.

We have identified TLK proteins as novel regulators of NHEJ repair and PARPi sensitivity in BRCA1-depleted cells, suggesting that TLK repression may represent a previously unrecognized mechanism by which BRCA1 mutant cancers acquire PARPi resistance.

In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have targeted for several years and novel approaches.

(2) The enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation...(5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by the TMPRSS2-ERG oncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors in the long term, which may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found to accumulate following prolonged ENZ treatment, are still suppressed by the concomitant addition of J54.

Overall, this study provides new insights into TLK1 inhibition for GBM therapy. Collectively, these findings indicate that TLK1 is one of the upregulated kinases in GBM and phenothiazine-based TLK1 inhibitors could be a promising treatment option for GBM patients.

TLK1 phosphorylation is an important event in DUV irradiation. DUV irradiation combined with TLK1 inhibition has therapeutic potential in pancreatic cancer cells.

In addition, circTLK1 interacted with miR-876-3p, and SRSF7 was concluded to be the target gene of miR-876-3p. In this study, we researched the inhibitory effect of circTLK1knockdown on NSCLC progression and immune escape, and further elucidated the potential regulatory mechanism of circTLK1/miR876-3p/SRSF7 axis.

Collectively, our findings identify the TLK1-ASF1 pathway as a novel mediator of inflammatory signaling and a promising therapeutic target for AML treatment across diverse genetic subtypes. Selective inhibition of this pathway offers potential opportunities to intervene effectively, address intratumoral heterogeneity, and ultimately improve clinical outcomes in AML.

The findings of the present study indicated that TLK1 plays a crucial role in GC progression and is, therefore, promising as a therapeutic target against this disease.