Cotargeting DNA topoisomerase II enhances efficacy of RAS-targeted therapy in KRAS-mutant cancer models - PubMed
6 days ago
- #KRAS G12C inhibitors
- #Cancer therapy
- #Topo IIα
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- Sotorasib and adagrasib are the first KRAS G12C inhibitors approved, but they show modest response rates and short durations.
- KRAS G12C inhibitors promote topoisomerase IIα (Topo IIα) degradation, leading to DNA damage and apoptosis in cancer cells.
- Elevated Topo IIα levels are found in sotorasib-resistant cell lines, and TOP2A manipulation affects resistance.
- Combining KRAS G12C inhibitors with Topo II inhibitors like VP-16 enhances efficacy, delays resistance, and reduces tumor growth.
- The study highlights Topo IIα's role in RAS-targeted therapy, suggesting combinatorial strategies for improved outcomes.
- Conflicts of interest include research support and advisory roles for pharmaceutical companies among the authors.