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Michał Mikula

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Open access Aug 2026

Integrated Multi-Omics and Interactome Analysis of CDK8 Inhibition Reveals Erythroid Differentiation Programs and Therapeutic Synergy with BET Blockade in AML

Highlights What are the main findings? CDK8 inhibition reduced STAT5 S726/731 phosphorylation and promoted differentiation-associated changes in an LSC-enriched TEX cell line AML model. CDK8–BET co-inhibition showed context-dependent synergy in AML cell lines and PDX-derived models. What are the implications of the main findings? CDK8 supports transcriptional and metabolic programs associated with immature AML states. CDK8–BET co-inhibition merits biomarker-guided preclinical evaluation. Abstract Acute myeloid leukaemia (AML) is a therapeutically challenging malignancy driven by the self-renewal, quiescence, and therapy resistance of leukaemic stem cells (LSCs). CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells with CD34+/pSTAT5-high LSC-like characteristics; however, the epigenetic and transcriptional consequences of CDK8 blockade and actionable combinatorial strategies remain incompletely defined. Using the TEX cell line, an LSC-enriched surrogate model, we performed time-resolved RNA-seq, whole-proteome and phosphoproteomics mass spectrometry (MS), and CUT&Tag chromatin profiling following treatment with RVU120 and CCT251921. CDK8 protein–protein interactions were mapped by co-immunoprecipitation MS across five AML models, and synergy with Pelabresib (BET inhibitor) or CB6644 (RUVBL1/2 inhibitor) was assessed by high-content screening in three cell lines and three patient-derived xenograft (PDX) models. Both inhibitors suppressed STAT5 phosphorylation, induced loss of the CD34+/CD38− LSC-enriched phenotype, and drove erythromegakaryocytic differentiation. Transcriptomic and proteomic responses were concordant, and CDK8 inhibition triggered widespread enhancer activation with redistribution of RNAP2, BRD3, and NFRKB. CDK8 combined with Pelabresib acted synergistically in MOLM-16 cells and two of three PDX models. These findings identify CDK8 as a transcriptional node of LSC-associated programs and provide a mechanistic rationale for combined CDK8-BET inhibition in molecularly defined AML subsets, which will require validation in functional LSC assays and primary specimens.

M. Statkiewicz, I. Rumieńczyk, U. Pakulska et al. · Cells · 0 citations

Review Aug 2026

Cancer Without a Map: Navigating Cancer of Unknown Primary Through Molecular Profiling.

Cancer of unknown primary (CUP) is a heterogeneous group of rare metastatic malignancies that lack an identifiable primary site. Molecular profiling has emerged as a tool to improve diagnostic accuracy, identify actionable alterations, and guide therapy. Relevant literature was identified through searches of PubMed, Scopus and Web of Science. We focused on tissue-of-origin (TOO) prediction, prognostic biomarkers, molecularly targeted therapy, and immunotherapy, synthesizing findings of clinical trials, meta-analyses, and cohort studies. Molecular analyses ranging from single‑gene assays to integrated multi‑omics (genomics, transcriptomics, proteomics and epigenomics) surveys enhance TOO determination, detect actionable DNA alterations and therapy selection. TOO-directed therapy has shown mixed survival benefit; however, integrating molecular data with clinical and pathological evaluation via multidisciplinary tumor boards seem to improve outcomes. Comprehensive genomic profiling enables targeted therapy for patients with actionable alterations such as MSI-high, TMB-high, BRAFV600E, NTRK, or RET fusions. Immunotherapy has shown promising activity, especially in biomarker-selected subgroups, although the predictive criteria remain heterogeneous. Molecular profiling is increasingly central in CUP management, supporting both diagnostic clarification and individualized treatment. Evidence indicates that molecularly guided therapy, particularly when integrated with clinicopathological data, can improve survival and expand treatment options beyond empirical chemotherapy. Future research should aim to optimize biomarker-driven strategies, standardize predictive assays, and improve access to advanced molecular diagnostics.

K. Tałasiewicz, Michał Mikula, Aleksandra Kapała · Critical reviews in oncology... · 0 citations