RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The RAS/RAF/MEK/ERK pathway is crucial in numerous cancers.
• Targeted therapies exist for BRAF V600E mutations but not for other RAS pathway alterations like non-V600E BRAF, NF1 loss, or oncogenic KRAS.

Purpose of the Study:

• To investigate the efficacy of SHP2 phosphatase inhibition using RMC-4550 in preclinical cancer models with specific oncogenic drivers.
• To elucidate the mechanism by which SHP2 inhibition affects RAS-GTP loading and downstream signaling.

Main Methods:

• Utilized human cancer models harboring RAS-GTP-dependent oncogenic BRAF, NF1 loss, or nucleotide-cycling oncogenic RAS.
• Administered RMC-4550, a small-molecule allosteric SHP2 inhibitor.
• Assessed the impact on RAS/RAF/MEK/ERK signaling and tumor growth.

Main Results:

• RMC-4550 demonstrated effectiveness in cancer models with oncogenic BRAF (class 3 mutants), NF1 loss, and KRAS G12C.
• SHP2 inhibition reduced RAS/RAF/MEK/ERK pathway activation.
• Disruption of SOS1-mediated RAS-GTP loading was identified as the mechanism of action.

Conclusions:

• SHP2 plays a critical role in activating the oncogenic RAS/MAPK pathway in cancers with specific BRAF, NF1, or KRAS alterations.
• SHP2 inhibition represents a potential therapeutic strategy for patients with these cancer types.