CDK Inhibition Impairs RNA Splicing: A Novel Therapeutic Approach for Merkel Cell Carcinoma

Abstract ID 96154 Poster Board 257 Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with a high case fatality rate. Currently, immune checkpoint inhibitors (ICI) are the first line of treatment for metastatic MCC, but 50% of patients do not achieve durable responses. To identify novel treatments for MCC, we screened 4,000 compounds for their ability to reduce MCC viability. Using the Area Under the Dose-Response Curve, we identified CDK inhibitors as efficacious against multiple MCC cell lines. In vitro studies demonstrated that CDK inhibition induced MCC cell death accompanied by cell size reduction, cell cycle arrest, DNA damage, and apoptosis. Further mechanistic studies using RNA-seq and phosphoproteomics in MCC cells surprisingly revealed that immediate effects of CDK inhibition included mRNA splicing defects resulting in accumulation of retained intron transcripts. In vivo, CDK inhibition significantly slowed tumor growth in a pre-clinical xenograft mouse model of MCC. Overall, our studies identified CDK inhibition as a promising novel treatment approach for MCC and support a clinical trial of CDK inhibitors in patients whose MCC has progressed despite ICI therapy.