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(Slides)

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Researchers have developed a novel RNA interference (RNAi) molecule called MYC/KRAS chimeric siRNA, which has shown potent activity in inhibiting the expression of the MYC and KRAS genes. The MYC and KRAS genes are both implicated in cancer progression and are common driver mutations in lung cancer.<br /><br />The researchers found that linking the MYC and KRAS siRNAs into a chimeric siRNA resulted in a significant increase in their silencing activity compared to using the individual siRNAs alone. They also discovered that the endosomal metabolism of the chimeric siRNA led to the formation of 5'-dT overhangs, which improved the potency of the molecule.<br /><br />In experiments using lung cancer cells, the researchers demonstrated that targeting both MYC and KRAS with the chimeric siRNA molecule dramatically reduced cancer cell viability and inhibited tumorigenic potential. They also found that delivering the chimeric siRNA with an EGFR-targeting moiety improved tumor control and had better pharmacokinetics and pharmacodynamics.<br /><br />Lung cancer is the leading cause of cancer-related death worldwide, and the identification of key driver mutations like KRAS and MYC has led to targeted therapies that improve patient survival. However, the development of KRASG12C mutant-targeting inhibitors has shown only modest clinical response rates with rapid acquired resistance, underscoring the need for improved therapies.<br /><br />The researchers also observed that mutant KRAS and MYC signaling are highly coupled in cancer progression, and dual suppression of both genes can have a synergistic anticancer effect. This has been previously observed in mouse models of lung and breast cancer.<br /><br />Overall, the findings of this study suggest that the MYC/KRAS chimeric siRNA holds promise as a potential therapeutic strategy for targeting both MYC and KRAS in lung cancer, and further studies are warranted to explore its efficacy and safety in preclinical and clinical settings.

Asset Subtitle

Yogitha Chareddy

Meta Tag

Speaker Yogitha Chareddy

Topic Metastatic NSCLC: Targeted Therapy - KRAS/MET

Keywords

RNA interference

MYC/KRAS chimeric siRNA

gene expression inhibition

cancer progression

lung cancer

driver mutations

endosomal metabolism

5'-dT overhangs

cancer cell viability

tumor control