FLT3 mutations are frequently identified in acute myeloid leukemia (AML). In particular, FLT3-ITD is known to be an indicator of a poor prognosis. FLT3 inhibitors have improved the treatment outcomes of AML patients with mutated FLT3. However, several drug-resistance mechanisms have been reported, and new clinical strategies to overcome drug resistance are needed. Heat shock protein (HSP) 90 is a molecular chaperone that mediates the correct folding and functionality of its client proteins, including FLT3. In the present study, we investigated the effects of an HSP90 inhibitor on FLT3 inhibitor-resistant AML cells. Using MOLM-13 (an AML cell line harboring FLT3-ITD), we established FLT3-selective inhibitor (FI-700)-resistant cell lines with an FLT3 N676K mutation. An HSP90 inhibitor (17-AAG) inhibited the growth of the cell lines, and combination treatment with FI-700 and 17-AAG showed synergistic inhibition. The underlying mechanism is thought to be as follows: HSP90 inhibits the association between HSP90 and FLT3, and thus reduces the phosphorylation of FLT3 and its downstream signaling proteins, which induces the consequent degradation of FLT3. In summary, we demonstrated that the HSP90 inhibitor could inhibit the cell growth of FLT3 inhibitor-resistant AML cells. Our results suggest that HSP90 is a promising molecular target in relapsed/refractory AML.
