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

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.

• Authors: Kenichi Iwai, Masahiro Yaguchi, Kazuho Nishimura, Yukiko Yamamoto, Toshiya Tamura, Daisuke Nakata, Ryo Dairiki, Yoichi Kawakita, Ryo Mizojiri, Yoshiteru Ito, Moriteru Asano, Hironobu Maezaki, Yusuke Nakayama, Misato Kaishima, Kozo Hayashi, Mika Teratani, Shuichi Miyakawa, Misa Iwatani, Maki Miyamoto, Michael G Klein, Wes Lane, Gyorgy Snell, Richard Tjhen, Xingyue He, Sai Pulukuri, Toshiyuki Nomura
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 10 Issue 6 (06 2018) ISSN: 1757-4684 [Electronic] England
• PMID: 29769258 (Publication Type: Journal Article)
• Copyright: © 2018 Takeda Pharmaceutical Company Published under the terms of the CC BY 4.0 license.

Chemical References

• CLK inhibitor T-025
• Diamines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• Pyrimidines
• Quinolines
• Clk dual-specificity kinases
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Line, Tumor
• Diamines (chemistry, pharmacology)
• Genes, myc
• Humans
• Mice
• Mice, Transgenic
• Phosphorylation
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism, physiology)
• Pyrimidines (chemistry, pharmacology)
• Quinolines (chemistry, pharmacology)
• RNA Splicing (drug effects, genetics)