BioProject

Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. More...

Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to treatment, cancer cells can rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. However, the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state have not yet been clarified. Using 3D culture models of mutant-KRAS CRC cell lines with distinct KRAS dependencies, we show that cells sensitive to KRAS silencing present a unique response characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomic analysis revealed nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biological processes that were upregulated in these cells. Additionally, alterations in chromatin compaction and physical organization and in genome-wide DNA interactions were also observed, alongside enhanced transcriptional heterogeneity. Our findings provide evidence for an epigenetic mechanism leveraged by chromatin reorganization and transcriptional heterogeneity involved in the induction of tolerance to KRAS loss, which may underpin the remarkable ability of cancer cells to rapidly adapt, survive, and maintain their malignancy even when deprived of oncogenic KRAS. Such insights highlight novel therapeutic opportunities aimed at disrupting intrinsic or adaptive resistance, ultimately enhancing therapeutic outcomes. Overall design: To investigate the effect of KRAS inhibition in the transcription of colorectal cancer cell lines, we used 2 different KRAS mutant colorectal cancer cell lines (HCT116, LS174T and SW480). We then silenced cells using siRNA and performed gene expression profilling analysis using data obtained from RNA-seq of the different cell lines from silenced cells (siKRAS) or its control (siControl). Less...