NAT2 activity increases cytotoxicity of anthracycline antibiotics and HDAC inhibitors

The Arylamine- N -acetyltransferase-2 (NAT2) enzyme is involved in metabolism of commonly used drugs driving differences in efficacy and tolerability of treatments. To bridge the current knowledge gap on metabolism of cytotoxic drugs by NAT2, and identify anticancer agents whose effects depend on NAT2 activity, we assessed 147 clinically used drugs. Hit compounds were evaluated for metabolic conversion by acetylation in presence of recombinant NAT2. Among those 147 drugs we found doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat to have increased toxicity to cancer cells expressing the rapid NAT2 allele. Additionally, we report NAT2-mediated acetylation of idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101. These findings have implications for pharmacogenomics and cancer precision medicine using conventional chemotherapeutic drugs, as improving their efficacy and safety may affect >4 million cancer patients worldwide that receive these drugs as standard of care. • Drug metabolism has significant implications on efficacy and tolerability of cancer drugs. • NAT2 polymorphisms result into modified activity of the enzyme and coupled to increased toxicity of certain drugs. • 10 FDA approved cytotoxic compounds demonstrated increased toxicity to cancer cells with high NAT2 activity. • 5 anticancer drugs were directly acetylated by NAT2: doxorubicin, daunorubicin, idarubicin, vorinostat and CUDC-101. • Up to 4 million patients yearly may be impacted by these findings due to broad use of these drugs in cancer treatment