Dinaciclib inhibits mRNA processing in Merkel cell Carcinoma: a novel therapeutic with a unique mechanism of action

Authors

• Y Gera
• KE Savell
• OR Drake
• MB Brenner
• VA Lennon
• DQ Pham
• SJ Weber
• LE Komer
• L Wang
• K Schaefer
• FJ Rubio
• A Lemire
• ER Schreiter
• V Menon
• BT Hope
• R Madangopal

Abstract

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with a high fatality rate. Currently, immune check point inhibitors (ICI) are the first line of treatment for metastatic MCC, but over 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 dinaciclib, a CDK 1/2/5/9 inhibitor as efficacious against multiple MCC cell lines. In vitro studies demonstrated that dinaciclib induced MCC cell death accompanied by reduction in cell size, diminished S-phase, DNA damage, and apoptosis. Further mechanistic studies using RNA-seq and phosphoproteomics surprisingly revealed that the immediate effects of dinaciclib treatment in MCC cells included inhibition of mRNA splicing, resulting in an accumulation of retained intron transcripts. This rapid inhibition of RNA processing may account for the increased activity of dinaciclib over other CDK inhibitors. In vivo, dinaciclib was able to reduce tumor growth in a pre-clinical xenograft model of MCC. Overall, our studies identified dinaciclib as a promising novel treatment for metastatic MCC and support a clinical trial of this agent in patients whose MCC has progressed despite ICI therapy.

Scientific Focus Area: Molecular Pharmacology

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