SU11657 Cooperates with Doxorubicin To Increase Survival of Leukemic Mice.

Acute promyelocytic leukemia (APL) is characterized by t(15,17) resulting in fusion of RARα to PML; in rare cases, RARα may be fused to other partners. The PML-RARα fusion initiates APL-like disease in mice, including a response to ATRA. FLT3, a receptor tyrosine kinase, is mutated in a large number of human AMLs and roughly 40% of cases of human APL. In our mouse model of APL, we previously introduced activated FLT3 (ITD mutation) into bone marrow of PML-RARα transgenic mice and observed rapid development of AML. This disease is transplantable into sublethally irradiated mice with onset of disease between 3–6 weeks, creating a system suitable for therapeutic study.

There has been considerable effort focused on the development of small molecule inhibitors of FLT3 as therapeutics for hematological malignancies, in particular, AML; some of these inhibitors are currently in clinical trials. SU11657 is a multi-targeted inhibitor of class III/V receptor tyrosine kinases, including FLT3. We previously observed a synergistic effect of SU11657 in combination with ATRA in our PML-RARα/FLT3 model. We set out to use this model to assess the effectiveness of anthracycline chemotherapy in combination with SU11657. This model is in vivo resistant to the maximum tolerated dose of doxorubicin (3 mg/kg/day).

We found that the median survival of untreated and doxorubicin-treated mice with PML-RARα/FLT3 leukemia was not significantly different (42 and 45 days, respectively). SU11657 increased the median of survival to 55 days, whereas the combination therapy increased median survival to 62 days (P=0.003). Neither agent alone or in combination significantly increased survival of mice with PML-RARα leukemia lacking activated FLT3. These results suggest that the use of targeted therapeutics, such as a FLT3 inhibitor, can overcome chemoresistance to traditional therapies in AMLs.