Using high-throughput small molecule matrix screening to unlock novel therapeutic synergies in Merkel cell carcinoma

Authors

• KA Garman
• D Anastasakis
• T Gelb
• M Shen
• KC Cheng
• MD Hall
• M Hafner
• I Brownell

Abstract

Merkel cell carcinoma (MCC) is a rare and deadly skin cancer, with 80% of cases caused by Merkel cell polyomavirus (virus positive, VP-MCC) and 20% associated with UV-induced mutations. MCC responds to immunotherapy, but new treatments are needed as less than half of patients achieve durable responses.

We previously showed that VP-MCC overexpresses Bcl-xL and the Bcl-xL inhibitor navitoclax selectively kills VP-MCC. However, navitoclax’s clinical use is limited by dose-dependent thrombocytopenia. To address this, we sought to reduce the risk of thrombocytopenia by finding highly effective drug combinations that use lower doses of navitoclax. A synergy screen with 1900 compounds from the NCATS MIPE library revealed significant synergy between navitoclax and dinaciclib, a CDK inhibitor targeting CDK1/2/5/9/12.

In vitro, navitoclax monotherapy selectively triggered apoptosis in VP-MCC, while dinaciclib induced apoptosis in both MCC subtypes. Interestingly, RNA-seq and phosphoproteomics showed dinaciclib inhibited mRNA splicing in MCC cells. Furthermore, functional genomics demonstrated MCC cells are dependent on mRNA splicing. The combination of navitoclax and dinaciclib resulted in stronger inhibition of mRNA splicing, enhanced apoptosis, and more DNA damage. It also led to mRNA degradation and suppressed protein synthesis.

In a preclinical mouse model of MCC, a combination using low doses of each drug caused profound and sustained tumor shrinkage, with many tumors resolving completely. Importantly, improved survival was achieved without worsening thrombocytopenia.

In summary, our studies identified navitoclax and dinaciclib as a promising synergistic combination for MCC and uncovered mRNA splicing as a novel therapeutic vulnerability for this aggressive skin cancer.

Scientific Focus Area: Molecular Pharmacology

This page was last updated on Tuesday, August 6, 2024