Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Non-small-cell lung cancer (NSCLC) has high mortality due to limited drug response and resistance.
• Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in NSCLC and contributes to drug resistance.
• There is a critical need for novel NSCLC therapeutics targeting ROR1.

Purpose of the Study:

• To discover and characterize novel inhibitors of ROR1 for NSCLC treatment.
• To evaluate the efficacy of a newly identified ROR1 inhibitor, ARI-1, against NSCLC.
• To investigate ARI-1's mechanism of action and its potential in drug-resistant NSCLC.

Main Methods:

• Computer-aided drug design and cell-based screening were employed to identify ROR1 inhibitors.
• Biological evaluation of ARI-1 included assessing its targeting of ROR1's extracellular frizzled domain.
• In vitro and in vivo studies were conducted to evaluate ARI-1's effects on NSCLC proliferation, migration, and tumor growth, including its impact on PI3K/AKT/mTOR signaling.

Main Results:

• ARI-1 was identified as a novel ROR1 inhibitor, specifically targeting its extracellular frizzled domain.
• ARI-1 potently suppressed NSCLC cell proliferation and migration by regulating ROR1-dependent PI3K/AKT/mTOR signaling.
• ARI-1 demonstrated significant in vivo tumor growth inhibition with minimal toxicity and showed efficacy against EGFR-TKIs-resistant NSCLC cells overexpressing ROR1.

Conclusions:

• The ROR1 inhibitor ARI-1 is a promising novel drug candidate for NSCLC treatment.
• ARI-1 is particularly effective for EGFR-TKIs-resistant NSCLC with high ROR1 expression.
• Targeting ROR1 represents a viable therapeutic strategy for overcoming drug resistance in NSCLC.