Danusertib and bosutinib have synergistic activity in imatinib-resistant CML cells.
Major finding: A potent FLT3 inhibitor overcomes the differentiation block in patients with FLT3/ITD AML.
Approach: A clinical correlative study was performed using samples from patients enrolled in a phase II trial.
Impact: Kinase inhibitors can induce terminal differentiation of cancer cells.
Internal tandem duplication (ITD) mutations in fms-related tyrosine kinase 3 (FLT3) occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. Quizartinib is a potent inhibitor of the FLT3 receptor tyrosine kinase that is currently being evaluated in a phase II clinical trial for patients with FLT3/ITD AML. An interim analysis of this trial indicated that 71% of patients experienced a clinical response. Unexpectedly, although peripheral blasts were rapidly cleared, the patients' bone marrows remained hypercellular and bone marrow blasts continued to express FLT3/ITD. Sexauer and colleagues hypothesized that quizartinib induced AML blast differentiation and therefore evaluated bone marrow and blasts collected before and during quizartinib treatment from of a subset of patients enrolled in this trial. After several weeks of treatment, a significant increase in the mature myeloid cell population and a dramatic decrease in the number of blasts were observed in the peripheral blood and bone marrow of 13 of the 14 patients and were typically associated with a complete response. Moreover, the myeloid cells still expressed the FLT3/ITD, suggesting that these cells were directly derived from leukemic precursors. Interestingly, the 1 patient who did not respond and a second patient who ultimately experienced disease progression each had mutations in CCAAT/enhancer binding protein α (C/EBPα), which may represent a potential mechanism of resistance to FLT3 inhibitors. Indeed, in an in vitro system in which FLT3/ITD–expressing AML cells were cocultured with bone marrow stromal cells, C/EBPα knockdown significantly decreased quizartinib-induced differentiation of AML cells. These findings indicate that FLT3 mutations block differentiation in AML and suggest that induction of terminal differentiation by kinase inhibitors may be an effective way to treat FLT3/ITD AML.
Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, et al. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood 2012 Sept 25 [Epub ahead of print].
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