Over the recent years we’ve witnessed the implementation of the so-called “epigenetic drugs” in the management of several cancer types. Among the epigenetic pharmacopeia, several histone deacetylase inhibitors (HDACI) have recently received FDA-approval for treating certain T-cell lymphoma subtypes. Yet, their relatively low efficacy in B-cell lymphoma patients demands a better understanding of their biological effects.
In light of this unresolved clinical need, our lab in collaboration with colleagues from the Helmholtz Institute of Munich and the McGill University in Montreal found that HDACIs induce metabolic changes in lymphoma cells, a discovery that might help to improve the efficacy of these drugs to treat B-cell lymphoma patients.
Since HDACIs affect a large list of non-histone proteins, among them metabolic enzymes, we explored their effects on the cellular metabolism of diffuse large B-cell lymphoma, the most common lymphoma. By employing metabolomics (i.e. the simultaneous analysis of hundreds of cell products), we discovered how the lymphoma cells become more dependent of certain metabolic pathway after HDACI-treatment. Specifically, after being treated with HDACIs, the surviving B-cell lymphoma cells become more reliant on choline phosphate to produce the intermediates that maintain oncogenic pathways in active state. Moreover, by treating the HDACI-surviving lymphoma cells with an inhibitor of the enzyme that produces choline phosphate this mechanism is blunted and lymphoma cells die.
With all, our work reveals the impact of HDACI on metabolism, and stresses the need to investigate the biological effects, beyond translation, of this class of drugs in order to be able to successfully implement them in clinics.
Article full text link: https://doi.org/10.1016/j.ebiom.2018.01.014