title: TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells.
abstract: Interaction of myeloma cells with the bone marrow microenvironment is mediated in large part through different cytokines, especially VEGF and IL6. These cytokines, especially IL6, leads to upregulation of the JAK/STAT pathway in myeloma cell, contributing to increased proliferation, decreased apoptosis, and acquired drug resistance. Here, we examined the preclinical activity of a novel JAK2 inhibitor TG101209. TG101209 induced dose- and time-dependent cytotoxicity in a variety of multiple myeloma (MM) cell lines. The induction of cytotoxicity was associated with inhibition of cell cycle progression and induction of apoptosis in myeloma cell lines and patient-derived plasma cells. Evaluation of U266 cell lines and patient cells, which have a mix of CD45 positive and negative cells, demonstrated more profound cytotoxicity and antiproliferative activity of the drug on the CD45+ population relative to the CD45- cells. Exploring the mechanism of action of TG101209 indicated downregulation of pJak2, pStat3, and Bcl-xl levels with upregulation of pErk and pAkt levels indicating cross talk between signaling pathways. TG101209, when used in combination with the PI3K inhibitor LY294002, demonstrated synergistic cytotoxicity against myeloma cells. Our results provide the rationale for clinical evaluation of TG101209 alone or in combination with PI3K/Akt inhibitors in MM.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Teresa
authors.initials: T
authors.lastname: Kimlinger
authors.forename: Jessica
authors.initials: J
authors.lastname: Haug
authors.forename: Michael
authors.initials: M
authors.lastname: Timm
authors.forename: Linda
authors.initials: L
authors.lastname: Wellik
authors.forename: Timothy
authors.initials: T
authors.lastname: Halling
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Sundararasan Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017493:Leukocyte Common Antigens; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D002867:Chromones; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D053614:Janus Kinase 2; D017493:Leukocyte Common Antigens; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C508600:IL6 protein, human; C494086:STAT3 protein, human; C522865:TG101209; D000096926:Benzenesulfonamides; C467484:VEGFA protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507924:JAK2 protein, human; C516769:PTPRC protein, human