Abstract P5-17-13: Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo

Abstract

Breast cancer (BC) is a complex and heterogenous disease, and various approaches have been used to classify BC into several subtypes to improve diagnostic and therapeutic outcomes. One of the features of BC is deregulated transcription, which allows for classification of the disease based on gene expression signature into four basic types: Luminal A, Luminal B, HER2-enriched, and triple negative (TNBC)/basal-like. Novel therapeutic approaches targeting oncogenic transcriptional programs may represent a promising strategy, in particular for TNBC, where the lack of common genetic alterations has so far limited the development of targeted therapies. The CDK8 module of the mediator complex represents an effective therapeutic target across multiple hematologic malignancies and solid tumors. CDK8 module of mediator functions as a master coordinator of transcription, bridging enhancers and core promoters. Meta-analysis of transcriptomic data revealed that higher CDK8 expression and its paralog CDK19 is associated with shorter relapse-free survival (RFS) in all molecular subtypes of BC. Our analysis of curated TCGA data revealed that >15% of all BC have alterations in either CDK8 or CDK19. Increased expression of CDK8 in BC can be partially attributed to copy number gains and amplifications. High CDK8 expression was inversely correlated with the expression of estrogen receptor (ER) and positively correlated with occurrence of TP53 mutations. In order to identify whether increased expression of CDK8/19 in BC could be associated with increased sensitivity to pharmacological inhibition of both kinases, we have interrogated a panel of BC cell lines representing various subtypes with RVU120 - a specific, selective inhibitor of CDK8/CDK19, currently being tested in a first-in-human Phase Ib clinical trial. The highest sensitivity to RVU120 in clonogenic assays has been observed for TNBC and ER-/PR-/HER2+ cells with high STAT3 phosphorylation levels. In contrast, neither RVU120 nor other CDK8 inhibitors were able to inhibit mitogenic effect of estrogen, confirming differential efficacy in hormone - independent BC. Detailed transcriptional profiling of responder cells revealed high enrichment of TNF/NFKB and STAT target genes (signatures associated with inflammatory phenotypes) and SOX4 target genes (signatures associated with invasiveness and stemness). Non-responder cells were characterized by enrichment of transcriptional signatures of ER activity. Efficacy of RVU120 in TNBC cells has been corroborated in a three-dimensional (3D) spheroid viability assay that could predict in vivo efficacy of RVU120 in tested xenograft models and recapitulated using other chemically non-related CDK8 inhibitors, indicating a class effect. Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. These studies provide rationale for further development of RVU120 in TNBC patients. Citation Format: Tomasz Rzymski, Aniela Gołas, Milena Mazan, Urszula Pakulska, Magdalena Masiejczyk, Agata Stachowicz, Justyna Martyka, Michał Combik, Katarzyna Wiklik, Kristina Goller, Marta Obacz, Elżbieta Adamczyk, Krzysztof Brzózka. Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-13.

Seize the engine: Emerging cell cycle targets in breast cancer

“…The inhibition of other CDKs such as CDK8/19 and CDK9 has demonstrated preclinical efficacy in BC, including models of TNBC and of endocrine‐ and CDK4/6i‐resistant HR + /HER2 − –BC, but this strategy has not yet rendered clinical data. 90 , 91 , 92 , 93 In particular, more than 15% of breast tumours harbour alterations in CDK8/19, mostly copy number gains, and its expression is inversely correlated with ER expression and relapse‐free survival. 91 …”

“… 90 , 91 , 92 , 93 In particular, more than 15% of breast tumours harbour alterations in CDK8/19, mostly copy number gains, and its expression is inversely correlated with ER expression and relapse‐free survival. 91 …”