Despite heterogeneity deregulated transcription is one of the universal features of leukemia cells. This has paved the way for the development of active compounds targeting epigenetic and transcriptional factors. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. In many cancer cells SEL120-34A regulates expression of STAT1- dependent genes as a major transcriptional effect. In AML cells regulation of NUP98-HOXA9 - dependent transcription and other transcriptional programs involved in maintenance of leukemia stem cells have been observed as a dominant mechanism of action. Treatment with the compound resulted in a differential efficacy on CD34 positive AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. Prolonged exposure of AML cells lines to chemotherapy led to the enrichment in population of resistant CD34 positive cells, which proved to be oversensitive to SEL120-34A treatment, providing rationale for rational combinations with approved drugs. Further clinical development of SEL120-34A is warranted as a novel therapeutic approach in relapsed and refractory AML.
Citation Format: Eliza Majewska, Milena Mazan, Michal Mikula, Agnieszka Dreas, Katarzyna Wiklik, Aniela Golas, Katarzyna Wojcik, Magdalena Masiejczyk, Malgorzata Statkiewicz, Urszula Kuklinska, Krzysztof Goryca, Aleksandra Grochowska, Aleksandra Cabaj, Michal Combik, Jerzy Ostrowski, Krzysztof Brzozka, Tomasz Rzymski. CDK8 inhibitor SEL120-34A targets CD34 positive AML cells by regulation of various transcriptional programs involved in maintenance of leukemia stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5829.