title: Development of rituximab-resistant B-NHL clones: an in vitro model for studying tumor resistance to monoclonal antibody-mediated immunotherapy.
abstract: Therapeutic strategies for cancer include chemotherapy, immunotherapy, and radiation. Such therapies result in significant short-term clinical responses; however, relapses and recurrences occur with no treatments. Targeted therapies using monoclonal antibodies have improved responses with minimal toxicities. For instance, Rituximab (chimeric anti-CD20 monoclonal antibody) was the first FDA-approved monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma (NHL). The clinical response was significantly improved when used in combination with chemotherapy. However, a subset of patients does not respond or becomes resistant to further treatment. Rituximab-resistant (RR) clones were used as a model to address the potential mechanisms of resistance. In this chapter, we discuss the underlying molecular mechanisms by which rituximab signals the cells and modifies several intracellular survival/antiapoptotic pathways, leading to its chemo/immunosensitizing activities. RR clones were developed to mimic in vivo resistance observed in patients. In comparison with the sensitive parental cells, the RR clones are refractory to rituximab-mediated cell signaling and chemosensitization. Noteworthy, interference with the hyperactivated survival/antiapoptotic pathways in the RR clones with various pharmacological inhibitors mimicked rituximab effects in the parental cells. The development of RR clones provides a paradigm for studying resistance by other anticancer monoclonal antibodies in various tumor models.
authors.affiliation: Department of Surgery, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. AJazirehi@mednet.ucla.edu
authors.forename: Ali R
authors.initials: AR
authors.lastname: Jazirehi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000069283:Rituximab; D050796:STAT3 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D000069283:Rituximab; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases