Comprehensive Review of ROS1 Tyrosine Kinase Inhibitors-Classified by Structural Designs and Mutation Spectrum...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• ROS1 fusion-positive non-small cell lung cancer (NSCLC) is rare but has multiple tyrosine kinase inhibitors (TKIs) available and in development.
• Approved ROS1 TKIs include crizotinib, entrectinib, and repotrectinib.
• Emerging resistance mutations, such as L2086F in the central beta-sheet region, pose challenges for current therapies.

Purpose of the Study:

• To categorize existing and developing ROS1 TKIs based on structural and inhibitory properties.
• To summarize clinical activity of ROS1 TKIs for guiding treatment decisions.
• To identify potential therapeutic strategies for overcoming resistance mutations, particularly the L2086F mutation.

Main Methods:

• Categorization of ROS1 TKIs by structural class (cyclic vs. noncyclic).
• Assessment of inhibitory activity against specific resistance mutations (G2032R and L2086F).
• Review and summarization of reported clinical activity and preclinical data for various TKIs.

Main Results:

• ROS1 TKIs were categorized by structure and activity against solvent front (G2032R) and Cβ6 (L2086F) mutations.
• The L2086F mutation confers resistance to next-generation ROS1 TKIs like repotrectinib and taletrectinib.
• Cabozantinib and potentially L-shaped type I TKIs (ceritinib, gilteritinib) show promise in overcoming L2086F-mediated resistance.

Conclusions:

• A dashboard approach to categorizing ROS1 TKIs can aid clinical decision-making.
• Cabozantinib and gilteritinib warrant further investigation for repurposing as ROS1 TKIs, especially for targeting the L2086F Cβ6 mutation.
• Future clinical trials should focus on evaluating cabozantinib and gilteritinib for efficacy against ROS1 L2086F mutations in NSCLC.