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

Iwai, Kenichi; Yaguchi, Masahiro; Nishimura, Kazuho; Yamamoto, Yoshiyuki; Tamura, Toshiya; Nakata, Daisuke; Dairiki, Ryo; Kawakita, Yoichi; Mizojiri, Ryo; Ito, Yoshikatsu; Asano, Masaharu; Maezaki, Hironobu; Nakayama, Yusuke; Kaishima, Misato; Hayashi, Kozô; Teratani, Mika; Miyakawa, Shuichi; Iwatani, Misa; Miyamoto, Maki; Klein, Michael G.; Lane, Wes; Snell, G.; Tjhen, Richard; He, Xingyue; Pulukuri, Sai Murali Krishna; Nomura, Toshiyuki

doi:10.15252/emmm.201708289

Cited by 69 publications

(99 citation statements)

References 55 publications

(76 reference statements)

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“…Identification of other genes/mRNA commonly regulated by CLK2 and MYC may help to understand the CLK inhibition vulnerability upon MYC induction. In fact, Iwai et al () only establish a clear correlation between both MYC amplification and a high expression of CLK2 in BCa, suggesting that a significant heterogeneity exists among tumor types in terms of molecular mechanistics. Hematological cancers also seem to benefit from CLK2 inhibition, although CLK2 or MYC did not sensitize these cells to T‐025, thus indicating that alternative mechanisms account for such effects.…”

Section: Overview Of As Modulation By Clk2 Myc and The T‐015 Inhibitormentioning

confidence: 99%

“…While Iwai et al () showed that T‐025 also inhibited DYRK1A, a kinase that has been postulated as a tumor suppressor in some cancers (Liu et al , ), they point out that DYRK1A depletion in cancer cells blunt T‐025 treatment effects. Moreover, response sensitivity to T‐025 treatment did not correlate with DYRK1A expression levels, implying that T‐025 acts mainly through CLK2 inhibition.…”

Section: Overview Of As Modulation By Clk2 Myc and The T‐015 Inhibitormentioning

confidence: 99%

“…Intriguingly, MYC ‐driven cancers present vulnerability against spliceosome inhibition. In this issue of EMBO Molecular Medicine , Iwai et al () tackle targeting the splicing regulatory Cdc2‐like kinase ( CLK s) family. They report that a novel, orally administered CLK 2 inhibitor (T‐025) induces exon skipping, which results in cancer cell growth reduction, especially in breast cancer ( BC a) MYC ‐driven tumors.…”

mentioning

confidence: 99%

“… F. Salvador and R. Gomis discuss the study by Iwai et al () in this issue of EMBO Molecular Medicine , on how targeting the splicing regulatory Cdc2‐like kinase (CLK) family offers alternative therapeutic options for treating aggressive MYC‐driven cancers.

…”

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confidence: 99%

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CLK 2 blockade modulates alternative splicing compromising MYC ‐driven breast tumors

Salvador

Gomis

2018

EMBO Mol Med

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MYC oncogene overexpression/amplification is common in multiple human cancers, in which it regulates proliferation, apoptosis and cell metabolism, among other processes, and its expression associates with poor prognosis. Targeting MYC presents an exciting therapeutic possibility, but developing appropriate drugs that impair protein function remains challenging. Searching for alternative therapeutic options for treating aggressive MYC‐driven cancers is thus of high clinical interest. Intriguingly, MYC‐driven cancers present vulnerability against spliceosome inhibition. In this issue of EMBO Molecular Medicine, Iwai et al (2018) tackle targeting the splicing regulatory Cdc2‐like kinase (CLKs) family. They report that a novel, orally administered CLK2 inhibitor (T‐025) induces exon skipping, which results in cancer cell growth reduction, especially in breast cancer (BCa) MYC‐driven tumors.

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Section: Overview Of As Modulation By Clk2 Myc and The T‐015 Inhibitormentioning

confidence: 99%

Section: Overview Of As Modulation By Clk2 Myc and The T‐015 Inhibitormentioning

confidence: 99%

mentioning

confidence: 99%

…”

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confidence: 99%

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CLK 2 blockade modulates alternative splicing compromising MYC ‐driven breast tumors

Salvador

Gomis

2018

EMBO Mol Med

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“…In PCa and other malignancies, mutations in genes coding for 63RBPs and changes in their expression levels have been observed 11,16 . Moreover, AS appears to 64 represent a cancer therapeutic vulnerability in leukaemia and breast cancer driven by the oncogenic 65 TF MYC [17][18][19] . MYC has also been shown to transcriptionally regulate expression of AS-associated 66 RBPs in lymphoma, lung cancer and glioma pre-clinical models 20-22 .…”

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confidence: 99%

Dysregulation of splicing-related proteins in prostate cancer is controlled by FOXA1

Foster

Arkell

Giudice

et al. 2018

Preprint

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29Prostate cancer (PCa) is genomically driven by dysregulation of transcriptional networks involving the 30 transcriptional factors (TFs) FOXA1, ERG, AR, and HOXB13. However, the role of these specific TFs 31 in the regulation of alternative pre-mRNA splicing (AS), which is a proven therapeutic vulnerability for 32 cancers driven by the TF MYC, is not described. Using transcriptomic datasets from PCa patients, 33we tested for an association between expression of FOXA1, ERG, AR, HOXB13, and MYC, and 34 genes involved in AS -termed splicing-related proteins (SRPs), which have pleiotropic roles in RNA 35 metabolism. We identified FOXA1 as the strongest predictor of dysregulated SRP gene expression, 36 which was associated with PCa disease relapse after treatment. Subsequently, we selected a subset 37 of FOXA1-binding and actively-transcribed SRP genes that phenocopy the FOXA1 dependency of 38 PCa cells, and confirmed in vitro via knockdown and over-expression that FOXA1 regulates SRP 39 gene expression. Finally, we demonstrated the persistence of a FOXA1-SRP gene association in 40 treatment-relapsed castration-resistant PCa (CRPCa) patients. Our data demonstrate, for the first 41 time, that FOXA1 controls dysregulated SRP gene expression, which is associated with poor PCa 42 patient outcomes. Analogous to MYC-driven cancers, our findings implicate the therapeutic targeting 43 of SRPs and AS in FOXA1-overexpressing PCa. 44 Running title 45 FOXA1 and splicing-related proteins in prostate cancer 46 Keywords 47Recently, widespread genomic and transcriptional dysregulation of genes encoding RNA-59 binding proteins (RBPs) have been reported across several cancers [11][12][13] . RBPs are a family of 60 proteins with pleiotropic roles in RNA metabolism including alternative pre-mRNA splicing (AS) 14 . 61Through the regulation of their target mRNAs, RBPs are associated with different oncogenic 62 processes and patient outcomes 15 . In PCa and other malignancies, mutations in genes coding for 63RBPs and changes in their expression levels have been observed 11,16 . Moreover, AS appears to 64 represent a cancer therapeutic vulnerability in leukaemia and breast cancer driven by the oncogenic 65 TF MYC [17][18][19] . MYC has also been shown to transcriptionally regulate expression of AS-associated 66 RBPs in lymphoma, lung cancer and glioma pre-clinical models 20-22 . However, little is known of the 67 mechanisms of transcriptional dysregulation of RBP expression in PCa. 68Here, we show that genes encoding RBPs and other proteins involved in AS (referred to, 69 hereafter, as splicing-related proteins; SRPs) are globally dysregulated in PCa, and identify the TF 70 FOXA1 as a key regulator of SRP gene expression. 71

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Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Hogg,

Findlay

2023

FEBS Letters

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Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

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

Cited by 69 publications

References 55 publications

CLK 2 blockade modulates alternative splicing compromising MYC ‐driven breast tumors

CLK 2 blockade modulates alternative splicing compromising MYC ‐driven breast tumors

Dysregulation of splicing-related proteins in prostate cancer is controlled by FOXA1

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

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