Inverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers

Area of Science:

• Oncology
• Molecular Biology
• RNA Interference Therapeutics

Background:

• Mutant KRAS drives a significant portion of human cancers.
• Existing therapies targeting KRASG12C show promise but require broader strategies for resistance and other mutations.
• MYC is a key downstream oncogene activated by KRAS, presenting a challenging therapeutic target.

Purpose of the Study:

• To develop a novel therapeutic strategy for simultaneous inhibition of KRAS and MYC.
• To evaluate the efficacy of an "inverted" chimeric RNAi molecule targeting both oncogenes.
• To establish proof-of-concept for ligand-directed, dual-silencing of KRAS and MYC in cancer models.

Main Methods:

• Development of an "inverted" chimeric RNAi molecule fusing MYC-targeting siRNA and KRAS-targeting siRNA.
• In vitro assessment of synergistic RNAi activity and cancer cell viability inhibition.
• In vivo studies utilizing EGFR-ligand conjugated chimeric siRNA for tumor cell delivery and assessment of tumor progression.

Main Results:

• The chimeric molecule demonstrated synergistic RNAi activity, leading to >10-40 fold improvement in inhibiting cancer viability in vitro.
• Ligand-conjugated chimeric siRNA showed enhanced metabolic stability, improved oncogene silencing, and reduced tumor progression in vivo.
• The dual-targeting approach significantly outperformed individual siRNA components.

Conclusions:

• The "inverted" chimeric RNAi design provides a potent strategy for simultaneously silencing KRAS and MYC.
• Ligand-directed delivery enhances therapeutic efficacy and tumor targeting.
• This approach offers a versatile platform for co-targeting any two genes of interest in cancer therapy.