Abstract LB_B21: Extracellular RNA signatures of mutant KRAS-driven lung cancer

Abstract RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Using both affinity- and nanofiltration-based EV isolation approaches, we show that specific TE RNAs, lncRNAs, and mRNAs, some of which are prognostic for lung adenocarcinoma (LUAD) patient survival, are preferentially released in extracellular vesicles (EVs). Moreover, we find that inhibition of oncogenic KRAS signaling broadly reprograms the noncoding transcriptome, as evidenced by a substantial increase in TE RNA secretion. Mutant KRAS inhibition also increases the abundance of secreted lncRNAs and retained intron-containing transcripts, while decreasing the mRNA content of EVs. Notably, oncogenic KRAS signaling is required for the secretion of mRNAs from a set of 20 genes that are significantly associated with unfavorable clinical outcomes in LUAD. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway. Our study also suggests that both coding and noncoding RNAs that are secreted in EVs may serve as mutant KRAS-specific signatures for diagnosing lung cancer via minimally invasive RNA liquid biopsy technology, which we are currently developing as a companion diagnostic for mutant KRAS-targeting therapies. Citation Format: Sree Lakshmi Velandi Maroli, Roman E Reggiardo, Reem Khojah, Daniel H Kim. Extracellular RNA signatures of mutant KRAS-driven lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B21.