Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Ras-mitogen activated protein kinase (MAPK) pathway deregulation is common in cancers and drives therapy resistance.
• Mutations in K-Ras often stabilize active RAF signaling complexes, sustaining pathway activity.
• Kinase Suppressor of Ras (KSR) acts as a MAPK scaffold, regulated by RAF dimerization.

Purpose of the Study:

• To develop small-molecule antagonists targeting KSR function.
• To explore KSR as a therapeutic target for overcoming Ras-driven cancers and resistance to targeted therapies.
• To investigate KSR's role in regulating MAPK signaling and its potential for drug development.

Main Methods:

• Developed KSR-targeting compounds based on mutations that selectively inhibit oncogenic Ras signaling.
• Utilized APS-2-79 as an exemplified compound to modulate KSR-dependent MAPK signaling.
• Assessed the impact of APS-2-79 on RAF heterodimerization, MEK phosphorylation, and KSR activation.
• Evaluated APS-2-79's efficacy in combination with MEK inhibitors in Ras-mutant cell lines.

Main Results:

• Identified a novel inactive KSR state stabilized by newly developed compounds.
• Demonstrated that APS-2-79 antagonizes RAF heterodimerization and MEK activation.
• Showed that APS-2-79 enhances MEK inhibitor potency in Ras-mutant cells by blocking negative feedback.
• Confirmed KSR conformational switching as a druggable regulator of oncogenic Ras signaling.

Conclusions:

• Targeting KSR by stabilizing its inactive state is a viable therapeutic strategy for Ras-driven cancers.
• Co-targeting scaffold (KSR) and enzymatic (RAF/MEK) components of the Ras-MAPK pathway can overcome resistance.
• Developing KSR antagonists like APS-2-79 holds promise for improving efficacy of current MAPK inhibitors.