Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion–Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia

It has been established in preclinical models of multiple myeloma and acute myeloid leukemia (AML) that the bone marrow microenvironment provides protection from chemotherapy- and death receptor–mediated apoptosis. This form of resistance, termed de novo drug resistance, occurs independent of chroni...

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Published in:	Clinical cancer research Vol. 12; no. 2; pp. 591 - 599
Main Authors:	YANAMANDRA, Niranjan, COLACO, Nandita M, PARQUET, Nancy A, BUZZER, Robert W, BOULWARE, David, WRIGHT, Gabriela, PEREZ, Lia E, DALTON, William S, BEAUPRE, Darrin M
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-01-2006
Subjects:	Acute Myeloid Leukemia Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences Bone Marrow - drug effects Bone Marrow - metabolism Boronic Acids - pharmacology Bortezomib Cell Adhesion - drug effects Drug Resistance, Neoplasm Drug Synergism Drug Therapy, Combination Farnesyl Transferase Inhibitors Fibronectins - metabolism Hematologic and hematopoietic diseases Humans Immunodeficiencies. Immunoglobulinopathies Immunoglobulinopathies Immunopathology Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Multiple Myeloma Multiple Myeloma - drug therapy Multiple Myeloma - metabolism Pharmacology. Drug treatments Proteasome Inhibitors Pyrazines - pharmacology Quinolones - pharmacology Stromal Cells - cytology Stromal Cells - drug effects Stromal Cells - metabolism Tumor Cells, Cultured Antineoplastic agent Immunopathology Bortezomib Enzyme Transferases Acute Enzyme inhibitor Tipifarnib Malignant hemopathy Myeloma Adhesion Farnesyl-diphosphate farnesyltransferase In vitro Synergism Immunoglobulinopathy Lymphoproliferative syndrome Multiple resistance Acute myelocytic leukemia
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Summary:	It has been established in preclinical models of multiple myeloma and acute myeloid leukemia (AML) that the bone marrow microenvironment provides protection from chemotherapy- and death receptor–mediated apoptosis. This form of resistance, termed de novo drug resistance, occurs independent of chronic exposure to cancer-related therapies and likely promotes the development of multidrug resistance. Consequently, it is of major interest to identify compounds or drug combinations that can overcome environment-mediated resistance. In this study, we investigated the activity of tipifarnib (Zarnestra, formerly R115777) combined with bortezomib (Velcade, formerly PS-341) in microenvironment models of multiple myeloma and AML. The combination proved to be synergistic in multiple myeloma and AML cell lines treated in suspension culture. Even in tumor cells relatively resistant to tipifarnib, combined activity was maintained. Tipifarnib and bortezomib were also effective when multiple myeloma and AML cells were adhered to fibronectin, providing evidence that the combination overcomes cell adhesion–mediated drug resistance (CAM-DR). Of importance, activation of the endoplasmic reticulum stress response was enhanced and correlated with apoptosis and reversal of CAM-DR. Multiple myeloma and AML cells cocultured with bone marrow stromal cells also remained sensitive, although stromal-adhered tumor cells were partially protected (relative to cells in suspension or fibronectin adhered). Evaluation of the combination using a transwell apparatus revealed that stromal cells produce a protective soluble factor. Investigations are under way to identify the cytokines and/or growth factors involved. In summary, our study provides the preclinical rationale for trials testing the tipifarnib and bortezomib combination in patients with multiple myeloma and AML.
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ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-05-1792