Dinaciclib impairs mRNA splicing: unlocking new vulnerability in merkel cell carcinoma

Summary: Abstract Body: Merkel cell carcinoma (MCC) is a rare, aggressive, and often fatal skin cancer. The majority of MCC cases are caused by Merkel cell polyomavirus (virus-positive, VP-MCC), while a smaller subset is driven by UV-induced mutations (virus-negative, VN-MCC). Immune checkpoint inhibitors (ICI), the current first-line treatment for metastatic MCC, yield durable responses in fewer than 50% of patients, underscoring the need for novel therapies. To explore new treatment options, we employed multimodal high-throughput screening, including pharmacologic and functional genomics screens. Our pharmacologic screen identified dinaciclib, a CDK1/2/5/9 inhibitor, as cytotoxic against MCC cell lines regardless of viral status. In all MCC cell lines, dinaciclib induced apoptosis at 72 hours, and this apoptosis was accompanied by the downregulation of the antiapoptotic factors MCL1, Bcl-xL, and XIAP. Intriguingly, dinaciclib inhibited mRNA splicing within 5 hours of treatment. This splicing inhibition was initially identified through phosphoproteomics and subsequently validated using ribosome-depleted RNA-seq and differential splicing analysis. Interestingly, RNA-seq also revealed dinaciclib increased mRNA degradation, suggesting a dual mechanism affecting RNA dynamics in MCC cells. Functional genomics further confirmed the critical role of mRNA splicing in MCC viability, as knockdown of key splicing factors led to cell death across both VP-MCC and VN-MCC cell lines. In a preclinical xenograft model of MCC, dinaciclib significantly suppressed tumor growth without adverse effects on body weight or other detectable toxicities. Overall, our study positions dinaciclib as a promising therapeutic candidate for MCC while identifying mRNA splicing inhibition as a novel and targetable pathway in the treatment of this aggressive cancer. Khalid A. Garman¹, Dimitrios Anastasakis², Tara Gelb¹, Min Shen³, Matthew D. Hall³, Markus Hafner², Isaac Brownell¹ 1. Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States. 2. RNA Molecular Biology Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States. 3. National Center for Advancing Translational Sciences, Bethesda, MD, United States. UV Biology/Injury and Non-melanoma Cancers