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

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. Overall design: Endometrial cancer cell lines were treated with the cell viability 50% inhibitory concentration (IC50) of Paclitaxel and SM08502 for 24 hrs. Ishikawa (Paclitaxel 11 nM; SM08502 80 nM); Ishikawa-S33Y (Paclitaxel 6 nM; SM08502 85 nM); SNGM (Paclitaxel 11.7 nM; SM08502 350.7 nM); HEC265 (Paclitaxel 5.6 nM; SM08502 149 nM). Differential gene expression and alternative splicing were measured. Please note that processed files for splicing analysis (rMATS) are for comparisons of samples, and therefore each sample has several processed files that are also shared with other samples as indicated in the corresponding sample description field.