Abstract
Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood. Here we found that inhibition of MYC transcription renders B-lymphoblastoid cells refractory to chemotherapeutic agents. This suggested that in the context of chemotherapy, stabilization of Myc protein could be more beneficial than its inactivation. We tested this hypothesis by pharmacologically inhibiting glycogen synthase kinase 3β (GSK-3β), which normally targets Myc for proteasomal degradation. We discovered that chemorefractory BL cell lines responded better to doxorubicin and other anti-cancer drugs when Myc was transiently stabilized. In vivo, GSK3 inhibitors (GSK3i) enhanced doxorubicin-induced apoptosis in BL patient-derived xenografts (BL-PDX), as well as in murine MYC-driven lymphoma allografts. This enhancement was accompanied by and required deregulation of several key genes acting in the extrinsic, death-receptor-mediated apoptotic pathway. Consistent with this mechanism of action, GSK3i also facilitated lymphoma cell killing by a death ligand TRAIL and by a death receptor agonist mapatumumab. Thus, GSK3i synergizes with both standard chemotherapeutics and direct engagers of death receptors and could improve outcomes in patients with refractory lymphomas.
Highlights
Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine
We found that knockout of either DR4 or DR5 did not affect the IC50 of DMSO+Dox compared to the scrambled control; in DR4 or DR5 KO lines, Fig. 5 glycogen synthase kinase 3β (GSK-3β) inhibition alters extrinsic apoptosis genes. a Volcano plot of KEGG apoptosis genes derived from RNA-Seq data on Ramos cells treated for 3 h with 3 μM CHIR99021 in biological triplicates
Our studies using murine allografts and human Burkitt lymphoma (BL) cell lines and PDXs demonstrate the benefits of adding GSK3 inhibitors to chemotherapeutic drugs in the R-CHOP/EPOCH-R regimens
Summary
Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. It is thought to be most effective in cancers with a single dominant genetic event, of which Burkitt lymphoma (BL) is a prime example. BL is an aggressive subtype of non-Hodgkin’s lymphoma that arises from germinal center B-cells [1]. The cytogenetic hallmark of BL is the t(8;14) chromosomal translocation that results.
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