Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Receptor d'origine nantais (RON, MST1R) is a receptor tyrosine kinase (RTK) implicated in various cancers.
• The role of RON splicing variants in tumorigenesis and therapeutic resistance remains largely unknown.

Purpose of the Study:

• Investigate the impact of RON splicing variants on colorectal cancer resistance to anti-EGFR therapy.
• Elucidate the oncogenic mechanisms of RON variants (Δ155, Δ160, Δ165).
• Evaluate the therapeutic potential of a novel RON inhibitor, WM-S1-030.

Main Methods:

• Analysis of colorectal cancer patient tissues for activated RON.
• Characterization of RON splicing variants (Δ155, Δ160, Δ165) in cancer cell lines.
• In vitro and in vivo efficacy studies of WM-S1-030 in solid tumor models.
• Investigation of RON-mediated signaling pathways (EGFR, Src, β-catenin) and immunomodulatory effects.

Main Results:

• Activated RON correlates with resistance to anti-EGFR therapy in colorectal cancer.
• RON variants Δ155, Δ160, and Δ165 act as tumor drivers.
• WM-S1-030 effectively inhibits RON variants and wild-type RON, leading to tumor regression.
• WM-S1-030 demonstrates antitumor immunity in an anti-PD-1 resistant model, potentially via macrophage polarization modulation.

Conclusions:

• WM-S1-030 exhibits potent antitumor activity against solid tumors expressing RON variants.
• The inhibitor shows potential for overcoming therapeutic resistance and enhancing immunotherapy.
• WM-S1-030 represents a promising new therapeutic strategy for cancers with specific RON variant expression.