2023 World Conference on Lung Cancer (Posters)-P2.11. Synergistic Co-Targeting Of MYC And KRAS In Lung Cancer By Novel Ligand-Directed Inverted Chimeric RNAi Molecules

P2.11. Synergistic Co-Targeting Of MYC And KRAS In Lung Cancer By Novel Ligand-Directed Inverted Chimeric RNAi Molecules - PDF(Abstract)

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This study explores the potential of targeting both KRAS and MYC genes in lung cancer using a novel ligand-conjugated oligonucleotide-based strategy. Non-small cell lung cancer (NSCLC) is often driven by mutations in the KRAS gene, which has proven difficult to target therapeutically. However, recent discoveries have led to the development of mutant-specific small-molecule inhibitors. Unfortunately, these inhibitors have shown limited clinical responses and acquired resistance. In this study, the researchers investigate the cooperation between mutant KRAS and MYC in promoting tumorigenesis and propose co-targeting these genes as a potential solution to overcome resistance.<br /><br />The researchers designed novel chimeric RNAi molecules by linking chemically modified siRNAs that target KRAS and MYC, which effectively inhibit downstream signaling and various cancer phenotypes. These chimeric siRNAs showed superior silencing of KRAS and MYC compared to individual siRNAs, leading to a significant decrease in cell viability and tumorigenic potential.<br /><br />The metabolism of the chimeric siRNA was found to occur primarily in lysosomal compartments and was DICER-independent. The researchers then conjugated the chimeric siRNA to an EGFR-targeting ligand, which showed increased uptake in EGFR-expressing cells. Treating lung cancer xenografts with the ligand-conjugated chimeric siRNAs resulted in enhanced tumor control compared to individual siRNAs.<br /><br />Overall, this study demonstrates the therapeutic potential of co-targeting KRAS and MYC in lung cancer using a ligand-directed inverted chimeric siRNA design. The approach significantly reduces the expression of the target genes and shows synergistic anti-cancer effects in multiple lung cancer models. This proof-of-concept has wide-ranging biological implications for co-targeting any two genes of interest in cancer treatment.

Asset Subtitle

Yogitha Chareddy

Meta Tag

Speaker Yogitha Chareddy

Topic Metastatic NSCLC: Targeted Therapy - KRAS/MET

Keywords

KRAS gene

MYC gene

lung cancer

ligand-conjugated oligonucleotide-based strategy

non-small cell lung cancer (NSCLC)

mutant-specific small-molecule inhibitors

co-targeting

chimeric RNAi molecules

EGFR-targeting ligand

synergistic anti-cancer effects