A ROR1 small molecule inhibitor (KAN0441571C) induced significant apoptosis of ibrutinib-resistant ROR1⁺ CLL cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Chronic lymphocytic leukemia (CLL) often overexpresses the receptor tyrosine kinase ROR1.
• Ibrutinib, a Bruton's tyrosine kinase inhibitor, is a standard CLL treatment but resistance can develop.
• Understanding resistance mechanisms and alternative therapeutic targets is crucial for effective CLL management.

Purpose of the Study:

• To evaluate the efficacy of a novel ROR1 inhibitor, KAN0441571C, in CLL cells, particularly those resistant to ibrutinib.
• To investigate the impact of ROR1 inhibition on ROR1 phosphorylation in CLL cells.
• To assess the combined effect of ROR1 inhibition and venetoclax in ibrutinib-resistant CLL.

Main Methods:

• Primary CLL cells were obtained from six patients before and after developing ibrutinib resistance.
• Cells were treated with the ROR1 inhibitor KAN0441571C, ibrutinib, and/or venetoclax.
• Apoptosis induction and ROR1 dephosphorylation were assessed.
• Synergistic effects of drug combinations were evaluated.

Main Results:

• The ROR1 inhibitor KAN0441571C induced apoptosis in ibrutinib-resistant CLL cells similarly to ibrutinib-sensitive cells.
• KAN0441571C treatment led to the dephosphorylation of ROR1.
• In one patient resistant to both ibrutinib and venetoclax, the ROR1 inhibitor was still effective.
• The combination of ROR1 inhibitor and venetoclax demonstrated synergistic apoptosis in ibrutinib-resistant CLL cells.

Conclusions:

• ROR1 inhibition is a promising therapeutic strategy for CLL, even in the context of ibrutinib resistance.
• Targeting ROR1 can overcome resistance to ibrutinib in CLL.
• Combination therapy with ROR1 inhibitors and venetoclax may offer enhanced efficacy for resistant CLL.