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Combination CDC-like kinase inhibition (CLK) and taxane therapy in CTNNB1-mutated endometrial cancer

ABSTRACT: SM08502 is a novel pan CDC-like kinase (CLK) inhibitor that targets mRNA splicing and is optimized for Wnt pathway inhibition. Previous evaluation of single agent CLK inhibition (SM04690) demonstrated inhibition of tumor progression and b-catenin/TCF transcriptional activity in CTNNB1-mutant endometrial cancer (EC). In-vitro analysis of SM08502 similarly decreases Wnt transcriptional activity and cellular proliferation while increasing cellular apoptosis. Examining transcriptomic analysis, SM08502 increases pathways involved in RNA metabolism and spliceosome. Examining alternative splicing (AS) events, SM08502 increased differential splicing compared to treatment with paclitaxel. AS regulation is an important post-transcriptional mechanism associated with the oncogenic process in many cancers, including EC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215975 | GEO | 2023/08/07

REPOSITORIES: GEO

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Combination CDC-like kinase inhibition (CLK) and taxane therapy in CTNNB1-mutated endometrial cancer

Project description:Combination CDC-like kinase inhibition (CLK) and taxane therapy in CTNNB1-mutated endometrial cancer

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Combination CDC-like kinase inhibition (CLK)/Dual-specificity tyrosine-regulated kinase (DYRK) and taxane therapy in <i>CTNNB1</i>-mutated endometrial cancer.

Project description:SM08502 (cirtuvivint) is a novel pan CDC-like kinase (CLK) and Dual specificity tyrosine kinase (DYRK) inhibitor that targets mRNA splicing and is optimized for Wnt pathway inhibition. Previous evaluation of single agent CLK/DYRK inhibition (SM04690) demonstrated inhibition of tumor progression and β-catenin/TCF transcriptional activity in CTNNB1-mutant endometrial cancer (EC). In-vitro analysis of SM08502 similarly decreases Wnt transcriptional activity and cellular proliferation while increasing cellular apoptosis. SM08502 is an active single-agent therapy with IC50's in the nanomolar range for all EC cell lines evaluated. Combination of SM08502 with paclitaxel has synergistic effect in vitro, as demonstrated by Combination Index <1, and inhibits tumor progression in four endometrial cancer models (HEC265, Ishikawa, Ishikawa-S33Y, and SNGM). In our in vivo mouse models, Ishikawa demonstrated significantly lower tumor volumes of combination vs SM08502 alone (Repeated Measures one-way ANOVA, p = 0.04), but not vs paclitaxel alone. HEC265, SNGM, and Ishikawa-S33Y tumors all had significantly lower tumor volumes with combination SM08502 and paclitaxel compared to single-agent paclitaxel (Repeated Measures one-way ANOVA, p = 0.01, 0.004, and 0.0008, respectively) or single-agent SM08502 (Repeated Measures one-way ANOVA, p = 0.002, 0.005, and 0.01, respectively) alone. Mechanistically, treatment with SM08502 increases alternative splicing (AS) events compared to treatment with paclitaxel. AS regulation is an important post-transcriptional mechanism associated with the oncogenic process in many cancers, including EC. Results from these studies have led to a Phase I evaluation of this combination in recurrent EC.

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CLK:BMAL1 is a pioneer-like transcription factor [CLK_ChIP]

Project description:The mammalian circadian clock relies on the master genes CLOCK (CLK) and BMAL1 and drives rhythmic gene expression to regulate biological functions under circadian control. We recently uncovered a surprising disconnect between the rhythmic binding of CLK:BMAL1 on DNA and the transcription of its target genes, suggesting that they are regulated by as yet uncharacterized mechanisms. Here we show that rhythmic CLK:BMAL1 DNA binding promotes rhythmic chromatin opening. The underlying mechanisms include CLK:BMAL1 binding to nucleosomes and rhythmic chromatin modifications, including the incorporation of the histone variant H2A.Z. This rhythmic chromatin remodeling mediates the rhythmic binding of other transcription factors adjacent to CLK:BMAL1, suggesting that the activity and the tissue-specific expression of these other transcription factors contribute to the genome-wide CLK:BMAL1 heterogeneous transcriptional output. These data therefore indicate that the clock regulation of transcription relies on the rhythmic regulation of chromatin accessibility and suggest that the concept of pioneer function extends to acute gene regulation, well beyond the current confines of developmental/cell specification.

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CLK:BMAL1 is a pioneer-like transcription factor [H2AZ-ChIP]

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CLK:BMAL1 is a pioneer-like transcription factor [MNase-Seq]

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CLK:BMAL1 is a pioneer-like transcription factor [CLK_ChIP]

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Transcription profiling of Drosophila S2 cells transfected with Clk

Project description:S2 cells transfected with pAc-Clk or empty vector Experiment Overall Design: S2 cells transfected with pAc-Clk or empty vector. Cells were transfected and RNA collected after 48hs

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Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression in an rs5918762 allele-dependent manner (ONT long read sequencing)

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