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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 functions as a master coordinator of transcription, bridging enhancers and core promoters. Meta-analysis of curated TCGA data reveals that >15% of all BC have increased expression of CDK8 and/or CDK19, and that elevated expression of both genes is associated with decreased overall survival. High CDK8 expression is inversely correlated with the expression of estrogen receptor (ER) and positively correlated with occurrence of TP53 mutations. RVU120 is a specific, low nM, selective inhibitor of CDK8/CDK19, currently being tested in a first-in-human Phase Ib clinical trial in patients with metastatic or advanced solid tumors progressing from previous lines of therapy (ClinicalTrials.gov: NCT05052255). In order to establish a rationale for treatment of BC with RVU120 we have interrogated a panel of cell lines representing various subtypes of BC. These studies revealed that TNBC and ER-/PR-/HER2+ cells were highly sensitive to RVU120 and also to two other non-related CDK8/19 inhibitors, indicating a class effect. In contrast, CDK8/19 inhibitors were not able to inhibit mitogenic effect of estrogen, confirming differential efficacy in hormone - independent BC. Detailed transcriptional profiling of RVU120-responder cells revealed high enrichment of STAT3 target genes, SOX4 target genes and gene hallmarks of epithelial to mesenchymal transition (EMT), signatures associated with invasiveness and stemness. Non-responder cells were characterized by enrichment of transcriptional signatures of ER activity. Further proteomic profiling show that the top responder cells were the Mesenchymal Stem-Like (MSL) molecular subtype of TNBC and were positive for transactivated pSTAT3. Transcriptomic RNAseq profiling of MSL TNBC cell lines indicated that among genes inhibited by RVU120 there was high enrichment of STAT1 (interferon signature), STAT3 (IL6- signaling) and STAT5 (IL2 signaling) dependent genes. Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. Overall, these studies provide rationale for further development of RVU120 in TNBC patients. Citation Format: Urszula Pakulska, Marta Obacz, Aniela Gołas, Milena Mazan, Magdalena Masiejczyk, Agata Stachowicz, Justyna Martyka, Michał Combik, Kinga Kęska, Katarzyna Wiklik, Kristina Goller, Elżbieta Adamczyk, Krzysztof Brzózka, Tomasz Rzymski. RVU120, a selective CDK8/CDK19 inhibitor, demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2647. |
