Abstract 5716: CDK7 as a drug target in advanced stage uveal melanoma

Abstract

Abstract Uveal melanoma (UM) metastasizes predominantly to the liver, and most metastatic UM are BAP1-deficient. Targeted therapies, such as MEK inhibitors, have failed clinically. There are few FDA-approved therapies for metastatic UM, but these therapies are limited to only a subset of patients and have modest survival benefits. Hence, there is a need to identify novel and effective treatment strategies. Due to the low mutational burden in UM, targeting transcriptional may be an effective strategy. Here, we identified Cyclin Dependent Kinase 7 (CDK7), a key regulator of transcription, as an essential and druggable target in UM. CDK7 directly phosphorylates RNA polymerase II and is expressed in all UMs. siRNA-mediated knockdown of CDK7 decreased the growth of three BAP1-deficient UM cell lines. We tested a clinically relevant, highly specific CDK7 inhibitor, SY-5609, developed by Syros Pharmaceuticals and similarly showed that the cell lines were sensitive to the growth inhibitory effects of SY-5609. Furthermore, we observed synergistic effects on cell growth inhibition when combined with a MEK inhibitor (Trametinib). We performed RNA sequencing and identified several Hallmark Genesets to be positively enriched, including interferon-gamma response, TGF-beta signaling, and NFκB signaling after treatment with SY-5609. These results are validated using a multi-omic approach, utilizing Reverse Phase Protein Array (RPPA) data to validate transcriptome to proteome expression of these enriched pathways. Overall, our studies indicate that targeting CDK7 in uveal melanoma is a potential treatment strategy for BAP1-deficient UM and enhances MEK inhibitor efficacy. Citation Format: Francis J. Waltrich. CDK7 as a drug target in advanced stage uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5716.