title: Transcriptomic rationale for the synergy observed with dasatinib + bortezomib + dexamethasone in multiple myeloma.
abstract: Despite the advantage observed with novel drugs such as bortezomib, thalidomide, or lenalidomide, multiple myeloma (MM) remains incurable and there is a clear need for new drugs or combinations based on the pathogenetic mechanism of MM. One of the proposed mechanisms in MM pathogenesis is the involvement of kinase molecules in the growth and survival of myelomatous cells. In this study, we have explored the optimal combination for dasatinib, a tyrosine kinase inhibitor, in MM cells. A clear synergistic effect was observed with the triple combination of dasatinib with bortezomib and dexamethasone which was evident even in the presence of bone marrow microenvironment. Experiments performed on freshly isolated patients' cells also demonstrated potentiation of response in the triple as compared with the agents alone or in double combinations. Gene expression profiling experiments provided some clues on the transcriptional rationale underlying this potentiation, as the triple combination led to significant deregulation of genes involved in cell death, cell growth, proliferation, DNA replication, repair and recombination, and cell-cell signaling. Some of these results were further confirmed by apoptosis and cell cycle experiments and also by Western blot and PCR. These data provide the rationale for the use of this novel combination in MM patients.
authors: Centro de Investigación del Cáncer, IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.
authors: Edvan
authors: E
authors: de Queiroz Crusoe
authors: Patricia
authors: P
authors: Maiso
authors: Diego
authors: D
authors: Fernandez-Lazaro
authors: Laura
authors: L
authors: San-Segundo
authors: Mercedes
authors: M
authors: Garayoa
authors: Antonio
authors: A
authors: Garcia-Gomez
authors: Norma C
authors: NC
authors: Gutierrez
authors: Manuel
authors: M
authors: Delgado
authors: Enrique
authors: E
authors: Colado
authors: Jesus
authors: J
authors: Martin-Sanchez
authors: Francis Y
authors: FY
authors: Lee
authors: Enrique M
authors: EM
authors: Ocio
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D020869:Gene Expression Profiling; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D013844:Thiazoles; D000069286:Bortezomib; D003907:Dexamethasone; D000069439:Dasatinib