The anti-myeloma effects of the selective JAK1 inhibitor (INCB052793) alone and in combination in vitro and in vivo
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.
KeywordsMultiple myeloma Janus kinase inhibitor Tumor In vivo Xenograft
We gratefully acknowledge Tanya M. Spektor and Jenna Riehl for reviewing of the manuscript.
JRB has received consulting fees, honoraria and research support for clinical and laboratory research from Incyte Corporation, whom also supported this study by research/study funding (INCY#24378).
Compliance with ethical standards
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). All institutional and national guidelines for the care and use of laboratory animals were followed. Informed consent was obtained from all patients for being included in the study. All animal studies were conducted according to the protocols approved by the Institutional Animal Care and Use Committee (approval no. 13.006).
Conflict of interest
This research was supported by a grant from Incyte Corporation. J. Berenson is a consultant/advisory board member for Incyte Corporation.
- 1.De Vos J, Jourdan M, Tarte K et al (2000) JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br J Haematol 109:823–828CrossRefGoogle Scholar
- 9.Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G, Dalton WS, Jove R (1999) Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10:105–115CrossRefGoogle Scholar
- 13.Uchiyama H, Barbut BA, Mohrbacher AF et al (1993) Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 82:3712–3720Google Scholar
- 14.Klein B, Zhang XG, Yang LZ et al (1995) Interleukin-6 in human multiple myeloma. Blood 85:863–874Google Scholar
- 16.Rawat R, Rainey J, Thompson CD et al (2000) Constitutive activation of STAT3 is associated with the acquisition of an interleukin 6-independent phenotype my murine plasmacytomas and hybridomas. Blood 96:3514–3521Google Scholar
- 17.Oshiro MM, Landowski TH, Catlett-Falcone R et al (2001) Inhibition of the JAK kinase activity enhances FAS- mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells. Clin Cancer Res 12:4262–4271Google Scholar
- 18.Zhang Z, Mao H, Du X et al (2016) A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway. Oncotarget 7:9296–9309Google Scholar
- 19.Li J, Favata M, Kelley JA, Caulder E, Thomas B, Wen X, Sparks RB, Arvanitis A, Rogers JD, Combs AP, Vaddi K, Solomon KA, Scherle PA, Newton R, Fridman JS (2010) INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support. Neoplasia 12:28–38CrossRefGoogle Scholar
- 20.Campbell RA, Berenson JR (2008) Animal models of multiple myeloma and their utility in drug discovery. Current Protocols in Pharmacology 40:14.9.1–14.9.22Google Scholar
- 21.Sanchez E, Li M, Kitto A, Li J, Wang CS, Kirk DT, Yellin O, Nichols CM, Dreyer MP, Ahles CP, Robinson A, Madden E, Waterman GN, Swift RA, Bonavida B, Boccia R, Vescio RA, Crowley J, Chen H, Berenson JR (2012) Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol 158:727–738CrossRefGoogle Scholar
- 22.Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J, on behalf of the International Myeloma Workshop Consensus Panel 1 (2011) Consensus recommendations for the uniform reporting of clinical trials: a report of the International Myeloma Workshop Consensus Panel 1. Blood 117:4691–4695CrossRefGoogle Scholar
- 25.Lu ZY, Brailly H, Wijdenes J, Bataille R, Rossi JF, Klein B (1995) Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments. Blood 86:3123–3131Google Scholar
- 27.Chen H, Li M, Sanchez E et al (2015) Increased alternative macrophage-2 (M2) polarization with Trib1 gene over expression in myeloma patients with progressive disease and Jak2 inhibitors reduce M2 polarization. Blood 126:1011Google Scholar
- 29.Chen H, Sanchez E, Li M et al (2014) Increased M2 macrophages in multiple myeloma patients with progressive disease and down-regulated polarization with the JAK2 inhibitor ruxolitinib. Blood 124:4106Google Scholar