1. The anticancer potential of the CLK kinases inhibitors 1C8 and GPS167 revealed by their impact on the epithelial-mesenchymal transition and the antiviral immune response.
- Author
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Shkreta L, Toutant J, Delannoy A, Durantel D, Salvetti A, Ehresmann S, Sauvageau M, Delbrouck JA, Gravel-Trudeau A, Comeau C, Huard C, Coulombe-Huntington J, Tyers M, Grierson D, Boudreault PL, and Chabot B
- Subjects
- Humans, Cell Line, Tumor, Antineoplastic Agents pharmacology, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases antagonists & inhibitors, Thiazoles pharmacology, Antiviral Agents pharmacology, HCT116 Cells, DEAD-box RNA Helicases metabolism, DEAD-box RNA Helicases genetics, Gene Expression Profiling, Epithelial-Mesenchymal Transition drug effects, Protein-Tyrosine Kinases metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics, Protein Kinase Inhibitors pharmacology, Cell Proliferation drug effects
- Abstract
The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167. Here, a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected. The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis.
- Published
- 2024
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