A pre-clinical study has suggested that antibiotics can be used to overcome resistance to a promising drug for acute myeloid leukaemia (AML).
Despite venetoclax being hailed as a successful treatment for some people with AML, a significant number of patients are already resistant to the treatment, and many of those who do initially respond develop resistance at a later stage.
To find out how to restore sensitivity to venetoclax in AML cells, Dr Steven Chan from the Princess Margaret Cancer Centre in Toronto, Canada, and colleagues first conducted a genetic screen. They found that the genes which, when inactivated, re-sensitised AML cells to the drug were all involved in the function of mitochondria – the energy producing organelles of cells. Specifically, the resistance genes were all involved in the machinery which produces proteins inside mitochondria.
The research team then tested the antibiotics tedizolid and doxycycline, which inhibit protein synthesis inside mitochondria, to see if they could overcome venetoclax resistance. In experiments using human AML cell lines resistant to venetoclax, they found that combining either of the antibiotics with venetoclax was more effective at killing AML tumour cells than venetoclax alone.
A triple combination of tedizolid, doxycycline, and venetoclax further enhanced the killing of resistant AML cells in vitro and in mice. The authors are now calling for the trio of drugs to be tested in clinical trials to see if they improve the outcomes of AML patients.
Lead researcher Dr Steven Chan said: “Venetoclax is a novel BCL-2 inhibitor that has shown tremendous promise in the treatment of AML, especially when used in combination with hypomethylating agents such as azacitidine. However, its efficacy is limited by the development of resistance.
“Using a functional genomics approach, we found that inactivation of genes involved in mitochondrial function can overcome resistance to venetoclax in AML cells. This finding has important clinical implications because several commonly-used antibiotics impair mitochondrial function in patients. We demonstrated that the addition of antibiotics, such as tedizolid and doxycycline, can effectively sensitise AML cells to venetoclax.
“Our study provides the rationale for investigating the combination of antibiotics and venetoclax in the treatment of AML patients.”
Sharon D, Cathelin S, Mirali S, Di Trani JM, Yanofsky DJ, Keon KA, Rubinstein JL, Schimmer AD, Ketela T, Chan SM (2019) “Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response”, Science Translational Medicine, doi: 10.1126/scitranslmed.aax2863
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