Research ArticleCancer

Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib

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Science Translational Medicine  09 Aug 2017:
Vol. 9, Issue 402, eaam8060
DOI: 10.1126/scitranslmed.aam8060

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Rock-a-bye bone marrow

Although chemotherapy saves the lives of many cancer patients, it is a difficult treatment that induces many major side effects, with one of the most common being myelosuppression (depletion of bone marrow cells). The consequences of myelosuppression include anemia, thrombocytopenia, and neutropenia, all of which can cause severe complications and delay subsequent courses of chemotherapy. Taylor et al. discovered that quizartinib, a tyrosine kinase inhibitor, can decrease the risk of myelosuppression during cancer treatment by transiently suppressing the proliferation of bone marrow progenitor cells. In contrast, cancer cells continue to proliferate during treatment, making them a target for chemotherapy even while the bone marrow is protected, as the authors demonstrated in mice with leukemia.

Abstract

We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.

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