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

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 cons...

Full description

Saved in:
Bibliographic Details
Main 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
Format: Article
Language:English
Published: Springer Nature 2018-05-01
Series:EMBO Molecular Medicine
Subjects:
alternative splicing
Cdc2‐like kinase inhibitor
CLK2
MYC
Online Access:https://doi.org/10.15252/emmm.201708289
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1757-4676
1757-4684

Similar Items