Oncotarget

Research Papers:

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

Lulzim Shkreta, Johanne Toutant, Aurélie Delannoy, David Durantel, Anna Salvetti, Sophie Ehresmann, Martin Sauvageau, Julien A. Delbrouck, Alice Gravel-Trudeau, Christian Comeau, Caroline Huard, Jasmin Coulombe-Huntington, Mike Tyers, David Grierson, Pierre-Luc Boudreault and Benoit Chabot _

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Abstract

Lulzim Shkreta1, Johanne Toutant1, Aurélie Delannoy1, David Durantel2, Anna Salvetti2, Sophie Ehresmann3, Martin Sauvageau3, Julien A. Delbrouck4, Alice Gravel-Trudeau4, Christian Comeau4, Caroline Huard5, Jasmin Coulombe-Huntington5, Mike Tyers5, David Grierson6, Pierre-Luc Boudreault4 and Benoit Chabot1

1 Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada

2 International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France

3 Institut de recherches cliniques de Montréal, Montréal, QC, Canada

4 Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Institut de Pharmacologie, Sherbrooke, QC, Canada

5 Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada

6 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

Correspondence to:

Benoit Chabot, email: [email protected]

Keywords: CLK kinases inhibitors; EMT; antiviral immune response; microtubules; metastasis

Abbreviations: EMT: Epithelial Mesenchymal Transition; EKO: Extended Knockout; GSEA: Gene Set Enrichment Analysis; TGF-β: Transforming Growth Factor β; PSI: Percent Splicing Index

Received: March 27, 2024     Accepted: May 06, 2024     Published: May 16, 2024

Copyright: © 2024 Shkreta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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