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Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma

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Science Translational Medicine  31 Jan 2018:
Vol. 10, Issue 426, eaan8723
DOI: 10.1126/scitranslmed.aan8723

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Doubling up against double-hit lymphoma

Double-hit lymphomas, a type of B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, are aggressive and difficult-to-treat tumors. In light of evidence showing that tigecycline, an antibiotic, may be effective against MYC-driven lymphomas, Ravà et al. combined it with venetoclax, a BCL2 inhibitor, to target the double-hit tumors. The authors found that the pair of clinically approved drugs showed synergy against the cancer and was also effective in combination with rituximab, a mainstay of current treatment for lymphoma.

Abstract

High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. BCL2 activation in mouse Eμ-myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.

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