A new ferrocene derivative blocks KRAS localization and function by oxidative modification at His95.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Ras proteins, particularly K-Ras, are crucial GTPases regulating cellular processes at the plasma membrane.
• Mutant K-Ras is a frequent driver in human cancers, including non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC).
• Ferrocene derivatives elevate reactive oxygen species (ROS) and have shown potential in inhibiting K-Ras-driven cancers.

Approach:

• Developed and tested a novel ferrocene derivative against K-Ras-dependent PDAC and NSCLC cell lines.
• Investigated the compound's effects on K-Ras plasma membrane binding, signaling, and cellular growth.
• Utilized antioxidant supplementation to confirm the role of ROS and identified specific amino acid residues involved in the mechanism.

Key Points:

• The novel ferrocene derivative effectively inhibited the growth of K-Ras-dependent PDAC and NSCLC.
• The compound specifically abrogated K-Ras plasma membrane binding and signaling, with effects reversed by antioxidants, indicating a ROS-mediated mechanism.
• K-Ras His95 residue in the G-domain was identified as critical for ferrocene-induced dissociation from the plasma membrane via oxidative modification.

Conclusions:

• The redox system directly regulates K-Ras plasma membrane binding and signaling through oxidative modification at the His95 residue.
• This study proposes a role for oncogenic mutant K-Ras in antioxidant-induced metastasis observed in K-Ras-driven lung cancers.
• The findings highlight a novel therapeutic avenue targeting K-Ras in specific cancers through redox modulation.