Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability.

EMBO Molecular Medicine
Kenichi IwaiToshiyuki Nomura

Abstract

The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T-025 treatment. MYC activation, which altered pre-mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti-tumor efficacy of T-025 in an allograft model of spontaneous, MYC-driven breast cancer, at well-tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially...Continue Reading

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Citations

Feb 19, 2019·Wiley Interdisciplinary Reviews. RNA·Patricia P ColtriGuilherme H G da Silva
Mar 16, 2019·Immunological Reviews·Andrea BissoBruno Amati
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Sep 15, 2021·Journal of Medicinal Chemistry·Zhen QinJinlei Bian
Sep 10, 2020·Cell Chemical Biology·Saiko ShibataMasatoshi Hagiwara

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Datasets Mentioned

BETA
GSE101541

Methods Mentioned

BETA
xenografts
xenograft
enzymatic assay
MDS
immunoprecipitation
transfection
PCR
transgenic

Software Mentioned

MISO
GraphPad prism
KINOME Scan
R
Cytoscape
Prism
GraphPad
TopHat
cBioPortal for Genomics
cBioPortal

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