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

ABSTRACT: ROR1 - a receptor tyrosine kinase - is overexpressed in CLL. Ibrutinib, a Bruton's tyrosine kinase inhibitor, is clinically effective in CLL but patients may develop resistance. We evaluated the effect of an ROR1 inhibitor, KAN0441571C, in CLL cells from six patients obtained before and after developing resistance to ibrutinib. The ROR1 inhibitor induced apoptosis in ibrutinib-resistant CLL cells to the same degree as in ibrutinib-sensitive cells and dephosphorylated ROR1. This was also noted in one patient who became resistant to both ibrutinib and the Bcl-2 inhibitor venetoclax. The combination of ROR1 inhibitor and venetoclax had a synergistic apoptotic effect on ibrutinib-resistant cells.

SUBMITTER: Ghaderi A

PROVIDER: S-EPMC9176142 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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A ROR1 small molecule inhibitor (KAN0441571C) induced significant apoptosis of ibrutinib-resistant ROR1<sup>+</sup> CLL cells.

Ghaderi Amineh A Okhovat Mohammad-Ali MA Wikanthi Layung Sekar Sih LSS Svensson Ann A Palma Marzia M Schultz Johan J Olin Thomas T Österborg Anders A Mellstedt Håkan H Hojjat-Farsangi Mohammad M

EJHaem 20210520 3

ROR1 - a receptor tyrosine kinase - is overexpressed in CLL. Ibrutinib, a Bruton's tyrosine kinase inhibitor, is clinically effective in CLL but patients may develop resistance. We evaluated the effect of an ROR1 inhibitor, KAN0441571C, in CLL cells from six patients obtained before and after developing resistance to ibrutinib. The ROR1 inhibitor induced apoptosis in ibrutinib-resistant CLL cells to the same degree as in ibrutinib-sensitive cells and dephosphorylated ROR1. This was also noted in ...[more]

PMID: 35844694

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