Midostaurin potentiates rituximab antitumor activity in Burkitt’s lymphoma by inducing apoptosis

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.

The multiple‐kinase inhibitor lenvatinib inhibits the proliferation of acute myeloid leukemia cells

“…Recently, the chemotherapy agents doxorubicin (DNR), mitoxantrone (Mito), etoposide or 2‐aminopurine‐6‐thiol (6‐TG) have become the preferred choices for AML treatment . Meanwhile, molecular‐targeted agents, eg midostaurin or enasidenib, have been approved for AML treatment and brought new hope for AML patients . Midostaurin, developed by Novartis Corporation, targets FLT3, c‐KIT, PDGFRB, VEGFR‐2 or protein kinase C; enasidenib, developed by Agios Corporation and Celgene Corporation, targets isocitrate dehydrogenase 2 (IDH2) to specifically inhibit the function of IDH2 mutants, reduces 2‐HG levels and reverses genomic hypermethylation status of AML .…”

“…Meanwhile, molecular‐targeted agents, eg midostaurin or enasidenib, have been approved for AML treatment and brought new hope for AML patients . Midostaurin, developed by Novartis Corporation, targets FLT3, c‐KIT, PDGFRB, VEGFR‐2 or protein kinase C; enasidenib, developed by Agios Corporation and Celgene Corporation, targets isocitrate dehydrogenase 2 (IDH2) to specifically inhibit the function of IDH2 mutants, reduces 2‐HG levels and reverses genomic hypermethylation status of AML . However, as clinical practical experience is accumulating, these agents have not led to the hoped‐for improvements in the survival of or prognosis for AML patients, suggesting that kinase inhibition may exert mild effects at the beginning of tumor development but lose its effect early on.…”

Xenograft models for pediatric cancer therapies

“…Subsequently, PDX BL models were generated from affected patient lymph nodes in athymic nude and SCID mice, demonstrating metastatic potential in SCID mice, but not in athymic nude mice 125 . These models have been used to study novel agents such as the pan-protein kinase C (PKC) inhibitor midostaurin with and without rituximab 71 , 126 . Promising results in preclinical models have led to ongoing clinical trials 71 .…”

“…These models have been used to study novel agents such as the pan-protein kinase C (PKC) inhibitor midostaurin with and without rituximab 71 , 126 . Promising results in preclinical models have led to ongoing clinical trials 71 .…”

Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis

“…In the process of TGF-β-induced epithelial–mesenchymal transition (EMT), CD59 is significantly upregulated by Smad3 to evade complement-mediated attack in metastasis ( 26 ). Further, we also found that the PKC signaling pathway is significantly activated in rituximab-resistant Burkitt’s lymphoma (BL) cells, and the application of the PKC inhibitor midostaurin could significantly enhance the pro-apoptotic effect of rituximab, leading to a significant therapeutic effect in tumor-bearing mouse models ( 27 ). Here, we demonstrate that NF-κB signaling axis is responsible for inducible CD59 expression in rituximab-resistant B-NHL cells and that inhibition of this axis can reduce CD59 expression and consequently sensitize rituximab-resistant B lymphoma cells to CDC effect.…”