Synthetic Lethality in Acute Myeloid Leukemia: A Focus on Dihydroorotate Dehydrogenase Inhibitors

Context The inhibition of Dihydroorotate Dehydrogenase (DHODH) was recently found to induce differentiation and apoptosis in acute myeloid leukemia (AML). Multiple clinical trials testing DHODH inhibitors are currently ongoing, but the clinical effectiveness of these compounds is expected to be lower than in vitro due to: i) the heterogeneity of the AML genetic landscape and the well-known ability of leukemic cells to undergo clonal escape when treated with single agents, and ii) the pyrimidine salvage pathway, which could mitigate the pyrimidine starvation induced by DHODH inhibitors. Objective To increase the apoptotic rate induced by DHODH inhibitors in AML cells by testing multiple associations both with classical chemotherapeutical agents and targeted compounds, leveraging the synthetic lethality concept. Design MEDS433, the DHODH inhibitor developed by our group, was tested on several AML cell lines (THP1, MV4-11, NB4, U937, OCI-AML3) and primary cells, alone and in combination with cytarabine, anthracyclines, and decitabine. Moreover, in order to block the pyrimidine salvage pathway, MEDS433 was also combined with dipyridamole, a potent inhibitor of hENT1 and hENT2 nucleotide/nucleoside transport channels. Results The association of MEDS433 with cytarabine, idarubicin, and decitabine resulted in an additive effect, with a significant increase of the apoptotic rate in all tested AML cell lines. Moreover, the combination of MEDS433 with dipyridamole resulted in a synergistic effect, with an apoptotic rate ranging between 69% and 95% after just 3 days of treatment at the lowest effective MEDS433 concentration (0.1 μM), depending on the cell line. The combination of MEDS433, dipyridamole, and chemotherapy resulted in the massive death of all AML cells (\u003e90%). The best associations were evaluated on primary cells, confirming optimal results. Conclusions The addition of DHODH inhibitors to the (3+7) regimen or to hypomethylating agents could significantly increase the performances of these classical treatments. Moreover, a deep pyrimidine starvation obtained through the inhibition of both DHODH and the pyrimidine salvage pathway, could further increase the antileukemic activity. Ongoing in vivo experiments will be determinant to verify this hypothesis and to assess the toxicity on normal cells. This work was supported by AIRC (IG-23344).