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

Abstract

High-grade B cell lymphomas with concurrent activation of the <i>MYC</i> and <i>BCL2</i> oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. <i>MYC</i> 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 <i>MYC</i>-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. <i>BCL2</i> activation in mouse Eμ-<i>myc</i> 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 <i>MYC/BCL2</i> 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.