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Science Translational Medicine  18 May 2016:
Vol. 8, Issue 339, pp. 339ec80
DOI: 10.1126/scitranslmed.aag0060

Patients with acute myeloid leukemia (AML), in contrast to those with chronic myeloid leukemia or acute promyelocytic leukemia (APML), have yet to benefit from targeted therapies directed at genetic aberrations that drive their cancers. One of the most common mutations in AML is FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD), which carries a particularly poor prognosis when treated with chemotherapy or stem cell transplant. Disappointingly, addition of a FLT3 inhibitor to chemotherapy for those with FLT3/ITD AML in clinical trials has not improved overall survival. One potential reason for this failure is that FLT3/ITD leukemia stem cells (LSCs) retain self-renewal capacity and may be less affected by FLT3 inhibition.

Ma and colleagues investigated the response of FLT3/ITD AML to FLT3 inhibitors plus all-trans retinoic acid (ATRA), a drug that induces differentiation of leukemic cells in APML. The authors hypothesized that ATRA could improve treatment of FLT3/ITD AML by differentiating LSCs, causing loss of self-renewal capacity. Using FLT3/ITD cell lines, they demonstrated that the combination of a FLT3 inhibitor and ATRA reduced AML proliferation in vitro compared with either drug alone. They also showed that expression of the anti-apoptosis protein BCL6 increased with FLT3 inhibition, helping explain the treatment’s ineffectiveness as monotherapy, but BCL6 normalized when ATRA was added. Next, they treated mouse FLT3/ITD AML xenografts with FLT3 inhibitors and ATRA, demonstrating a marked improvement in AML burden and survival compared with controls. Finally, they transplanted bone marrow from mice with FLT3/ITD AML into healthy, untreated mice. The mice that received donor marrow pre-treated with FLT3 inhibitor plus ATRA remained free of AML, indicating that combination therapy reduced or eliminated the pool of self-renewing LSCs.

This study illustrates two related principles. First, cancer clones, especially LSCs, frequently have redundant survival mechanisms, which may be why FLT3 inhibition alone does not eliminate AML. Second, inhibiting these redundant pathways with combination therapy may produce synergy even if the individual drugs are ineffective. Although studies in cancer xenograft models do not always translate directly to human patients, the lessons from this combination approach should be considered in planning clinical trials for AML and other cancers.

H. S. Ma et al., All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo. Blood 10.1182/blood-2015-05-646786 (2016). [Abstract]

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