ABSTRACT
Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.
Subject(s)
Chemokines, CXC/biosynthesis , Intracellular Signaling Peptides and Proteins/biosynthesis , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinases/metabolism , Lenalidomide/pharmacology , Mucin-1/biosynthesis , Multiple Myeloma/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Case-Control Studies , Chemokine CXCL12/biosynthesis , Chemokine CXCL12/metabolism , Chemokines, CXC/metabolism , Heterografts , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Janus Kinase 1/metabolism , Janus Kinase 2/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, SCID , Monocytes/drug effects , Monocytes/metabolism , Mucin-1/metabolism , Multiple Myeloma/blood , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/biosynthesis , Protein Serine-Threonine Kinases/metabolism , Receptors, CXCR4/biosynthesis , Receptors, CXCR4/metabolism , Signal Transduction , THP-1 CellsABSTRACT
The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Janus Kinase 1/antagonists & inhibitors , Multiple Myeloma/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/administration & dosage , Bortezomib/pharmacology , Cell Line, Tumor , Dexamethasone/administration & dosage , Dexamethasone/pharmacology , Drug Screening Assays, Antitumor , Drug Synergism , Lenalidomide/administration & dosage , Lenalidomide/pharmacology , Male , Mice, SCID , Molecular Targeted Therapy , Oligopeptides/administration & dosage , Oligopeptides/pharmacology , Protein Kinase Inhibitors/pharmacology , Specific Pathogen-Free Organisms , Xenograft Model Antitumor AssaysABSTRACT
B-cell maturation antigen (BCMA), a tumor necrosis factor receptor (TNFR) family member, is selectively expressed on terminally differentiated B-lymphocytes including multiple myeloma (MM) tumor cells. We sought to determine whether circulating (c)BCMA in MM serum interferes with antiBCMA antibody binding to MM cells. An enzyme-linked immunosorbent assay (ELISA) was used to determine serum (s) BCMA levels among 379 samples from patients with relapsed/refractory MM (RRMM). Furthermore, flow cytometric and immunofluorescent studies were used to examine if concentrations of BCMA in patients' serum were high enough to interfere with the binding of anti-BCMA antibody to MM tumor cells. We have shown that BCMA is elevated in the serum from MM patients and that the median concentration of sBCMA from RRMM patients was 176 ng/mL (n = 379). Additionally, there was a consistent decrease in the binding of anti-BCMA antibody to MM tumor cells with sBCMA level ≥156 ng/mL. Together, these results demonstrate that circulating BCMA levels in most RRMM patients are high enough to interfere with anti-BCMA antibody binding to MM tumor cells and may interfere with BCMA-targeted immune-based therapies.