Anti-tumor activity of orally available cyclic peptide LUNA18 through direct pan-RAS inhibition across diverse RAS...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Targeting RAS mutations beyond KRASG12C remains a significant challenge in cancer therapy.
• KRAS is a key driver in many cancers, but effective inhibitors for various mutations are limited.

Purpose of the Study:

• To introduce LUNA18 (paluratide) as a first-in-class pan-RAS GDP inhibitor.
• To evaluate LUNA18's efficacy against a broad spectrum of RAS mutations and its synergistic potential with other therapies.

Main Methods:

• In vitro testing of LUNA18 against cancer cells with various RAS alterations (G12, G13, KRAS amplification).
• Assessment of LUNA18's combination effects with RTK and MAPK pathway inhibitors.
• Evaluation of LUNA18's long-term signal inhibition compared to KRASG12C inhibitors.
• In vivo studies using xenograft models to assess anti-tumor effects.

Main Results:

• LUNA18 demonstrated potent inhibitory activity against diverse RAS mutations, including KRAS amplification.
• LUNA18 exhibited synergistic anti-tumor effects when combined with RTK and MAPK pathway inhibitors.
• LUNA18 achieved more potent and sustained MAPK pathway suppression than KRASG12C inhibitors, even with RAS wild-type inactivation.
• In xenograft models, LUNA18 combinations showed durable anti-tumor effects where KRASG12C inhibitors were limited.

Conclusions:

• LUNA18 is a promising first-in-class pan-RAS inhibitor with broad activity against various RAS mutations.
• LUNA18 offers enhanced and sustained MAPK pathway inhibition, suggesting superiority over KRASG12C inhibitors in certain contexts.
• LUNA18 represents a potential new therapeutic strategy for patients with RAS-driven cancers.