From cell lines to PDXs: in vivo confirmation of synergistic drug responses identified in leukemia cell line models.

Despite recent advances in clinical outcome for infants diagnosed with KMT2A-rearranged acute lymphoblastic leukemia (ALL), the development of more effective and less toxic induction therapies remains desirable. As this requires multidrug regimens, the identification of synergizing agents may be key for efficacy and in preventing toxicity. In search for drugs that strongly synergize against KMT2A-rearranegd ALL, we first conducted high-throughput combinatorial drug screens in cell line models. As a result, we found that any possible 2-drug combination of venetoclax, ponatinib, and trametinib was highly synergistic in vitro. The drug synergy was confirmed in vivo in a cell line-derived xenograft (CDX) mouse model but could not be validated in patient-derived primary KMT2A-rearranged infant ALL samples in vitro. Yet, in patient-derived xenograft (PDX) mouse models, drug synergy did emerge at a comparable level as observed in our CDX model. Regrettably, none of the synergistic 2-drug combinations appeared sufficiently effective in preventing leukemia outgrowth in our PDX models, which likely requires combinations of >2 drugs. Hence, our results illustrate/signify that straightforward high-throughput combinatorial drug screening in leukemia cell lines is a valid approach to identify synergistic drug combinations that are verifiable in vivo in PDX mouse models without requiring validation in primary patient cells in vitro.