CXCR2 As a Novel Target for Overcoming Resistance to Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia Cells

Abstract

Background: Chronic myeloid leukemia (CML) is a reciprocal translocation disorder driven by a breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) fusion gene that stimulates abnormal tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) are effective in the treatment of Philadelphia chromosome (Ph)+ CML patients. However, the appearance of TKI-resistant CML cells is a hurdle in CML treatment. Therefore, it is necessary to identify novel treatments that could target a different mechanism than that of tyrosine kinases. \n \nMethods: The study was designed to verify whether C-X-C chemokine receptor 2 (CXCR2) could be a novel target for TKI-resistant CML treatment. We examined CXCR2 ligands from CML patient samples and TKI-resistant CML cell lines. Then, we inhibited CXCR2 and examined the effects on cell proliferation and apoptosis using immunoblotting and flow cytometry. The CXCR2 inhibition effect was also confirmed using a mouse xenograft model with TKI-sensitive and -resistant CML cells. \n \nFindings: Interleukin 8 (IL-8), a CXCR2 ligand, was significantly increased in the bone marrow serum of initially diagnosed CML patients. CML cell lines expressed CXCR2, regardless of their sensitivity to TKIs. IL-8 stimulated CXCR2, mTOR, and c-Myc mRNA expression in CML cell lines. CXCR2 antagonists suppressed the proliferation of CML cells via cell cycle arrest in the G2/M phase. In addition, CXCR2 inhibition attenuated mTOR, c-Myc, and BCR-ABL expression, leading to CML cell apoptosis, irrespective of TKI responsiveness. Moreover, SB225002, a CXCR2 antagonist, caused higher cell death in CML cells than TKIs. Using a mouse xenograft model, we confirmed that SB225002 suppresses CML cells, with a prominent effect on TKI-resistant CML cells. \n \nInterpretation: Our findings demonstrate that IL-8 is a prognostic factor to the progress of CML. Inhibiting the CXCR2-mTOR-c-Myc cascade is a promising therapeutic strategy to overcome TKI-sensitive and -insensitive CML. Thus, CXCR2 blockade is a novel therapeutic strategy to treat CML, and SB225002, a commercially available CXCR2 antagonist, might be a drug candidate to treat TKI-resistant CML. \n \nFunding Statement: This study was supported by the Bio & Medical Technology Development Program of the National Research Foundation, which is funded by the Ministry of Science & ICT (2017M3A9C8060403). \n \nDeclaration of Interests: The authors declare that they have no competing interests. \n \nEthics Approval Statement: This study was approved by the internal review board of the Korea University Anam Hospital (IRB No. 2015AN0267).