What signals are generated by anti-CD20 antibody therapy?
Immunotherapy with rituximab (a chimeric anti-CD20 monoclonal antibody), alone or in combination with chemotherapy, has improved the treatment outcome of patients with non-Hodgkin's lymphoma (NHL), but the in vivo mechanisms by which rituximab exerts its effects have not been elucidated. The mechanisms underlying resistance are not known. In addition to the proposed actions mediated by rituximab (such as complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis), rituximab may signal the tumor cells and inhibit constitutively activated survival signaling pathways (Raf-1-MEK1/2-ERK1/2, p38 MAPK, NF-kappaB, and Akt), resulting in inhibition of cell growth and of selectively anti-apoptotic gene products such as Bcl-2 and Bcl-(xL). The inhibition of these anti-apoptotic gene products by rituximab sensitizes drug-resistant tumor cells to apoptosis induced by a variety of cytotoxic chemotherapeutic drugs. Also, rituximab sensitizes NHL cells to apoptosis resulting from upregulation of death receptors, implicating a novel in vivo role of host involvement in rituximab-mediated effects. We have developed rituximab-resistant clones that do not respond to rituximab-mediated cell signaling. The clones exhibited hyperactivated cell survival pathways and overexpression of anti-apoptotic gene products and could not be chemosensitized by rituximab. Inhibitors of the survival signaling pathways reverse drug resistance in both wildtype cells and resistant clones. These findings identify several novel intracellular pathways modifyed by rituximab that sensitize NHL cells to both chemotherapy and immunotherapy, as well as several therapeutic targets whose modifications reverse resistance. These findings have clinical relevance for both prognosis and novel treatment strategies for patients with NHL.
Bonavida
Benjamin
B
Dept. of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine at UCLA, Jonnson Comprehensive Cancer Center, University of California at Los Angeles, CA 90095-1747, USA. Bbonavida@mednet.ucla.edu
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000917:Antibody Formation / Q000187:drug effects; D018951:Antigens, CD20 / Q000276:immunology / Q000502:physiology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects*; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000502:physiology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D051020:bcl-X Protein; D000069283:Rituximab; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt