Identification and characterization of KRAS mutant specific drug combinations

Introduction: Oncogenic activation of KRAS is a key event in pancreatic carcinogenesis and a central driver of tumor progression and resistance. Remarkably, mutation-specific KRAS inhibitors are now in (pre)clinical testing and recent studies demonstrate a high specificity and efficacy of specific KRAS inhibitors. However, these studies also demonstrated a rapid development of resistance, often associated with transcriptional and metabolic reprogramming.

Objectives: This study investigates the alterations in chromatin landscape and molecular signaling pathways that drive cell adaptation and resistance against mutation-specific KRAS inhibitors. It also aims to identify and evaluate novel drug combinations through pre-clinical testing, with particular focus on compounds that target the activity of mitochondrial metabolic processes and cell defense strategies via control of oncogenes and metabolic signaling and transcription pathways (e.g. DNA binding complexes etc).

Methodology: To explore the drug-induced modifications in chromatin landscape and gene expression, we perform whole transcriptome analysis (RNA-seq), chromatin accessibility profiling (ATAC-seq) and genome-wide DNA binding studies (e.g. ChIP-seq) coupled with transcription factor complex formation studies and mitochondrial rewiring analysis. We further employ various molecular and physiological assays (e.g. BrdU, CellTiter-Glo, colony formation etc.) to assess tumor cell growth and cytotoxicity against the new drug combinations.

Results: Preliminary investigations revealed significant alterations in chromatin architecture in line with distinct set of transcription factors, gene signatures and signaling pathways that might enable tumor cells to adapt. These outcomes further suggest that tailored interference with mutant KRAS-specific transcription complexes not only affects transcriptional and metabolic rewiring processes but also counteracts survival strategies and resistance development.

Conclusion: Targeted inhibition of KRAS mutation-specific transcription complex formation and dependent molecular reprogramming might provide new and more effective strategies to enhance the efficacy of mutation-specific KRAS inhibitors. This study will help to identify central mechanisms of resistance against KRAS inhibitors and provide the basis for the development of novel therapeutic strategies

Publikationsverlauf

Artikel online veröffentlicht:
04. September 2025