Rzymski, T. | Search bioRxiv

bioRxiv2025

Romaciclib, a CDK8/CDK19 inhibitor, can overcome venetoclax resistance through a combinatorial strategy

The combination of venetoclax (VEN) and hypomethylating agents (HMA) is the standard of care in acute myeloid leukemia (AML) for elderly patients unfit for intensive chemotherapy. Despite its clinical success, most patients eventually relapse, creating an urgent need for effective therapeutic alternatives. In this study, we aimed to evaluate the potential of romaciclib, a first-in-class CDK8/CDK19 inhibitor, in combination with VEN to overcome stroma-mediated and primary/acquired VEN-resistance. We assessed the efficacy of RVU120+VEN combination in both sensitive and resistant AML cell lines and primary patient-derived models. Our finding demonstrated that romaciclib synergizes with VEN in AML cell lines and in 8 out of 11 patient-derived cell samples. The proteomic and functional studies demonstrated that combination induced apoptosis through caspase-dependent cleavage of MCL-1. In vivo studies confirmed the efficacy of RVU120+VEN, showing eradication of leukemic cells and bone marrow recovery. Importantly, the combination effectively overcame both stroma-mediated and transcriptionally dependent VEN-resistance. Mechanistic studies, focusing on transcriptomic analyses, identified key resistance-associated pathways, including IL6/JAK/STAT3, TGF-{beta}, PI3K/AKT/MTOR, and inflammatory signaling, being suppressed by combination treatment. Furthermore, an in vivo study using a VEN-resistant patient-derived xenograft (PDX) model confirmed the efficacy of the combination, demonstrating a significant reduction in leukemia burden and a decreased proportion of leukemia initiating cells (LIC) following treatment. These findings prove the highly synergistic mechanism of action of RVU120+VEN combination and the potential to overcome primary/acquired VEN resistance in relapse/refractory AML disease. Altogether, the presented results support ongoing clinical studies evaluating romaciclib and VEN in VEN/HMA-refractory patients (NCT06191263) and provide a basis for future exploration as a frontline therapy in VEN-naive patients.

cancer biology↗

bioRxiv2024

Transcriptional Regulation of Protein Synthesis by Mediator Kinase in MYC-driven Medulloblastoma

MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening across MB cell lines, we identified the Mediator-associated kinase CDK8 as the top dependence for MYC-driven MB. Loss of CDK8 markedly reduces MYC expression and impedes MB growth. Mechanistically, we demonstrate that CDK8 depletion suppresses ribosome biogenesis and mRNA translation. CDK8 regulates occupancy of phospho-Polymerase II at specific chromatin loci facilitating an epigenetic alteration that promotes transcriptional regulation of ribosome biogenesis. Additionally, CDK8-mediated phosphorylation of 4EBP1 plays a crucial role in initiating eIF4E-dependent translation. Targeting CDK8 effectively suppresses cancer stem and progenitor cells, characterized by increased ribosome biogenesis activity. We also report the synergistic inhibition of CDK8 and mTOR in vivo and in vitro. Overall, our findings establish a connection between transcription and translation regulation, suggesting a promising therapeutic approach targets multiple points in the protein synthesis network for MYC-driven MB.

cancer biology↗