Targeting the Receptor Tyrosine Kinase ROR1 by Small Molecules

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Receptor tyrosine kinases (RTKs) are crucial for tumor cell characteristics and are frequently dysregulated in cancers.
• Receptor tyrosine kinase like orphan receptor 1 (ROR1) is overexpressed in various hematological and solid tumors, promoting proliferation, survival, migration, and metastasis.
• While antibody-based therapies targeting ROR1 are in clinical trials, small molecule inhibitors offer an alternative therapeutic approach.

Purpose of the Study:

• To investigate the therapeutic potential of small molecule tyrosine kinase inhibitors (TKIs) targeting the intracellular domain of ROR1.
• To evaluate the efficacy of ROR1-TKIs in inhibiting ROR1 phosphorylation, downstream signaling pathways, and tumor growth.
• To explore the synergistic effects of ROR1-TKIs in combination with other cancer therapies.

Main Methods:

• Development and characterization of small molecules (KAN834/1571c, ARI-1, strictinin) that inhibit the tyrosine kinase (TK) domain of ROR1.
• Assessment of ROR1 phosphorylation inhibition and downstream WNT/β-catenin pathway modulation.
• Evaluation of ROR1-TKI-induced apoptosis in ROR1-positive tumor cells and cell lines.
• In vivo studies using animal models to assess tumor reduction and combination therapy effects with venetoclax.

Main Results:

• Small molecules KAN834/1571c, ARI-1, and strictinin effectively inhibited ROR1 kinase activity.
• ROR1-TKIs prevented ROR1 phosphorylation and inactivated both WNT/β-catenin dependent and independent pathways.
• Treatment with ROR1-TKIs induced apoptosis in patient-derived tumor cells and cell lines, and demonstrated dose- and time-dependent tumor reduction in animal models.
• A synergistic apoptotic effect was observed when ROR1-TKIs were combined with venetoclax.

Conclusions:

• Small molecule ROR1 inhibitors represent a promising novel therapeutic strategy for cancer treatment.
• Targeting the intracellular tyrosine kinase domain of ROR1 with small molecules effectively inhibits tumor growth and induces apoptosis.
• Further development of ROR1 small molecule inhibitors is warranted for inclusion in cancer therapy regimens.