Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-α fusion protein: Direct cytotoxicity and synergy with chemotherapy.

Abstract

Treatment of patients with B-NHL with rituximab and CHOP has resulted in significant clinical responses. However, a subset of patients develops resistance to further treatments. The mechanism of unresponsiveness in vivo is not known. We have reported the development of rituximab-resistant clones derived from B-NHL cell lines as models to investigate the mechanism of resistance. The resistant clones exhibit hyper-activated survival/anti-apoptotic pathways and no longer respond to a combination of rituximab and drugs. Recent studies reported the therapeutic efficacy in mice bearing B-cell lymphoma xenografts following treatment with the anti-CD20-hIFNα fusion protein. We hypothesized that the fusion protein may bypass rituximab resistance and inhibit survival signaling pathways. Treatment of the rituximab-resistant clones with anti-CD20-hIFNα, but not with rituximab, IFNα, or rituximab+IFNα resulted in significant inhibition of cell proliferation and induction of cell death. Treatment with anti-CD20-hIFNα sensitized the cells to apoptosis by CDDP, doxorubicin and Treanda. Treatment with anti-CD20-hIFNα inhibited the NF-κB and p38 MAPK activities and induced the activation of PKC-δ and Stat-1. These effects were corroborated by the use of the inhibitors SB203580 (p38 MAPK) and Rottlerin (PKC-δ). Treatment with SB203580 enhanced the sensitization of the resistant clone by anti-CD20-hIFNα to CDDP apoptosis. In contrast, treatment with Rotterin inhibited significantly the sensitization induced by anti-CD20-hIFNα. Overall, the findings demonstrate that treatment with anti-CD20-hIFNα reverses resistance of B-NHL. These findings suggest the potential application of anti-CD20-hIFNα in combination with drugs in patients unresponsive to rituximab-containing regimens.

• Authors: Gabriel G Vega, Luz Areli Franco-Cea, Sara Huerta-Yepez, Héctor Mayani, Sherie L Morrison, Benjamin Bonavida, Mario I Vega
• Journal: International journal of oncology (Int J Oncol) Vol. 47 Issue 5 Pg. 1735-48 (Nov 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 26398317 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD20
• Imidazoles
• Interferon-alpha
• Oncogene Proteins, Fusion
• Pyridines
• Rituximab
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Animals
• Antigens, CD20 (genetics, therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Imidazoles (administration & dosage)
• Interferon-alpha (genetics, therapeutic use)
• Lymphoma, B-Cell (drug therapy, genetics, pathology)
• Mice
• Oncogene Proteins, Fusion (genetics)
• Pyridines (administration & dosage)
• Rituximab (administration & dosage)
• p38 Mitogen-Activated Protein Kinases