Abstract
An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt’s lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells. The PI3K/AKT inhibitor IPI-145 failed to reverse the resistance. In contrast, the pan-PKC inhibitor midostaurin exhibited potent antitumor activity in both original and resistant cells, alone or in combination with rituximab. Notably, midostaurin promoted apoptosis by reducing the phosphorylation of PKC and consequently of downstream Bad, Bcl-2 and NF-κB. Therefore, midostaurin improved rituximab activity by supplementing pro-apoptotic effects. In vivo, midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments. Addition of midostaurin to rituximab led to dramatically improved survival compared to rituximab but not midostaurin monotherapy. Our findings call for further evaluation of midostaurin alone or in combination with rituximab in treating resistant BL in particular.
Highlights
Burkitt’s lymphoma (BL), a highly aggressive non-Hodgkin’s B-cell lymphoma, accounts for 3–5% of lymphoma cases in all age groups and 40–50% of all childhood lymphomas[1]
The intrinsic features of immune cells precipitate the resistance to rituximab-mediated ADCC20, while apoptosis plays a negligible role in rituximab antitumor activity
Using immunoblotting (Fig. 1a, c) and fluorescence-activated cell sorting (FACS) (Fig. 1b, d) assays, we found that CD20 expression decreased while CD59 expression increased in both resistant cell lines compared to the expression levels in the corresponding original cells (Fig. 1)
Summary
Burkitt’s lymphoma (BL), a highly aggressive non-Hodgkin’s B-cell lymphoma, accounts for 3–5% of lymphoma cases in all age groups and 40–50% of all childhood lymphomas[1]. Adult BL patients have shown a poor response to a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based regimen, with 2-year and 5-year overall survival (OS) rates of approximately 50–65%, decreasing to less than 30% with bone marrow or central nervous system involvement[2,3]. The combination of rituximab with CHOP chemotherapy (R-CHOP) has improved overall survival by at least 20% in cases of diffuse large B-cell lymphoma (DLBCL)[10]. Many single-arm clinical trials have confirmed the effect of adding rituximab to the intensive short-term chemotherapy regimens for BL11–15. A recent phase III clinical trial has shown that addition of rituximab to chemotherapy achieved better 3-year event-free survival (75% vs 62%, P = 0.024) and 3-year OS
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