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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2018-05-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201708289 |
| _version_ | 1827015143027900416 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kenichi Iwai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:59:41Z |
| format | Article |
| id | doaj.art-5f979a579b0246ad90c5cfcded6e406d |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:47Z |
| publishDate | 2018-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-5f979a579b0246ad90c5cfcded6e406d2024-10-28T08:56:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-05-0110611510.15252/emmm.201708289Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerabilityKenichi Iwai0Masahiro Yaguchi1Kazuho Nishimura2Yukiko Yamamoto3Toshiya Tamura4Daisuke Nakata5Ryo Dairiki6Yoichi Kawakita7Ryo Mizojiri8Yoshiteru Ito9Moriteru Asano10Hironobu Maezaki11Yusuke Nakayama12Misato Kaishima13Kozo Hayashi14Mika Teratani15Shuichi Miyakawa16Misa Iwatani17Maki Miyamoto18Michael G Klein19Wes Lane20Gyorgy Snell21Richard Tjhen22Xingyue He23Sai Pulukuri24Toshiyuki Nomura25Oncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedOncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedIntegrated Technology Research Laboratories, Takeda Pharmaceutical Company, LimitedIntegrated Technology Research Laboratories, Takeda Pharmaceutical Company, LimitedIntegrated Technology Research Laboratories, Takeda Pharmaceutical Company, LimitedIntegrated Technology Research Laboratories, Takeda Pharmaceutical Company, LimitedBiomolecular Research Laboratories, Takeda Pharmaceutical Company, LimitedBiomolecular Research Laboratories, Takeda Pharmaceutical Company, LimitedDrug Metabolism & Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company, LimitedDepartment of Structural Biology, Takeda California Inc.Department of Structural Biology, Takeda California Inc.Department of Structural Biology, Takeda California Inc.Department of Structural Biology, Takeda California Inc.Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co.Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co.Oncology Drug Discovery Unit, Takeda Pharmaceutical Company, LimitedAbstract 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.https://doi.org/10.15252/emmm.201708289alternative splicingCdc2‐like kinase inhibitorCLK2MYC |
| spellingShingle | 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 Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability EMBO Molecular Medicine alternative splicing Cdc2‐like kinase inhibitor CLK2 MYC |
| title | Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability |
| title_full | Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability |
| title_fullStr | Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability |
| title_full_unstemmed | Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability |
| title_short | Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability |
| title_sort | anti tumor efficacy of a novel clk inhibitor via targeting rna splicing and myc dependent vulnerability |
| topic | alternative splicing Cdc2‐like kinase inhibitor CLK2 MYC |
| url | https://doi.org/10.15252/emmm.201708289 |
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