期刊
CLINICAL CANCER RESEARCH
卷 14, 期 15, 页码 4925-4934出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-07-5072
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- Cancer Research UK Funding Source: Medline
- Worldwide Cancer Research [04-0427] Funding Source: Medline
Purpose: The use of targeted radiation therapy (RT) in conjunction with anti-CD20 monoclonal antibodies (mAb) delivers high clinical response rates in B-cell lymphomas as part of radioimmunotherapy. The mechanisms underlying these impressive responses, particularly in patients whose lymphomas have become refractory to chemotherapy, are poorly understood. Experimental Design: In this study, we have investigated the signaling pathways and mode of cell death induced in B-cell lymphoma cells after the combination of RT and either type I (rituximab) or type II (tositumomab/B1) anti-CD20 mAb. Results: Increased tumor cell death was observed when RT was combined with tositumomab, but not rituximab. This additive cell death was found to be mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-dependent and could be reversed with mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors, as well as small interfering RNA targeting MEK1/2. Furthermore, we found that this increased death was associated with ERK1/2 nuclear accumulation after tositumomab treatment, which was enhanced in combination with RT. Importantly, although Bcl-2 overexpression resulted in resistance to RT-induced apoptosis, it had no effect on the tumor cell death induced by tositumomab plus RT, indicating a nonapoptotic form of cell death. Conclusions: These findings indicate that RT and type II anti-CD20 mAb combine to stimulate a prodeath function of the MEK-ERK1/2 pathway, which is able to overcome apoptotic resistance potentially explaining the efficacy of this modality in treating patients with chemoresistant disease.
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