RRC ID 65722
Author Iwai K, Yaguchi M, Nishimura K, Yamamoto Y, Tamura T, Nakata D, Dairiki R, Kawakita Y, Mizojiri R, Ito Y, Asano M, Maezaki H, Nakayama Y, Kaishima M, Hayashi K, Teratani M, Miyakawa S, Iwatani M, Miyamoto M, Klein MG, Lane W, Snell G, Tjhen R, He X, Pulukuri S, Nomura T.
Title Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability.
Journal EMBO Mol Med
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 for MYC-driven cancer patients.
Volume 10(6)
Published 2018-6-1
DOI 10.15252/emmm.201708289
PII emmm.201708289
PMID 29769258
PMC PMC5991599
MeSH Animals Cell Line, Tumor Diamines / chemistry Diamines / pharmacology* Genes, myc Humans Mice Mice, Transgenic Phosphorylation Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Protein Serine-Threonine Kinases / antagonists & inhibitors* Protein Serine-Threonine Kinases / metabolism Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / metabolism Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism Proto-Oncogene Proteins c-myc / physiology Pyrimidines / chemistry Pyrimidines / pharmacology* Quinolines / chemistry Quinolines / pharmacology* RNA Splicing / drug effects* RNA Splicing / genetics
IF 8.821
Human and Animal Cells 293T(RCB2202)