Targeting the SHOC2-RAS interaction in RAS-mutant cancers.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Activating mutations in rat sarcoma (RAS) genes are common oncogenic drivers in human cancers.
• While KRAS inhibitors are emerging, effective therapies for NRAS(Q61*) mutants, prevalent in melanoma, are still needed.

Purpose of the Study:

• To identify dependencies in RAS(Q61*) tumors.
• To discover and develop novel therapeutic agents targeting the SHOC2-RAS interaction.

Main Methods:

• Identified SHOC2 as a dependency in RAS(Q61*) tumors.
• Utilized X-ray co-crystal structure to elucidate the NRAS(Q61R)-SHOC2 interaction.
• Performed in vitro high-throughput screening to discover small molecules targeting SHOC2.
• Conducted structure-based optimization to develop a tool compound.

Main Results:

• SHOC2 was identified as a dependency in a nucleotide-state-dependent and isoform-agnostic manner.
• A direct interaction between oncogenic NRAS(Q61R) and SHOC2 was confirmed via X-ray crystallography.
• Small molecules inhibiting the SHOC2-NRAS(Q61*) interaction were discovered.
• A tool compound demonstrated inhibition of MAPK signaling and proliferation in RAS-mutant cancer models, particularly NRAS(Q61*).

Conclusions:

• The SHOC2-RAS protein interaction is a druggable target for cancer therapy.
• This study provides a foundation for developing novel therapies targeting the RAS signaling pathway.
• Targeting SHOC2 offers a promising strategy for treating NRAS-mutant cancers.