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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]

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

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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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