Inhibition of FLT3-induced signalling in refractory acute myeloid leukaemia

Mutations in FLT3 make this receptor tyrosine kinase overactive. Such mutations found in ∼30 % of the patients who suffer from acute myeloid leukaemia (AML). FLT3 mediates signalling networks that lead to cell proliferation and survival. FLT3 inhibitors are used to treat AML but patients who are treated with them typically become resistant. Such resistance often emerges through secondary mutations which either restore the activity of FLT3 in the presence of drugs or activate a key player in a signalling network such as NRAS. We had developed AML-specific cell lines resistant to two advanced FLT3 inhibitors: gilteritinib and FF-10101. Resistance in these cell lines proceeds though different mechanisms. In this study, we followed on the efficacy of five FLT3 inhibitors (gilteritinib, FF-10101 and three promising inhibitors that are being developed), two pan-PI3K inhibitors (one of which also inhibits mTOR) and two c-KIT inhibitors in order to examine the significance of different signalling cascades in FLT3⁺-AML. In addition, we used molecular modelling and quantum chemistry calculations to explain why specific FLT3 mutations affect some inhibitors more than others. Two novel FLT3 inhibitors were found to be only weakly affected by resistance mutations against gilteritinib and FF-10101. The efficacy of most FLT3 inhibitors was only weakly (or not at all) affected by the NRAS/G12C activating mutation. Finally, no non-FLT3 inhibitor has shown sufficient efficacy in the cells, suggesting the central role of FLT3 in FLT3-mutated AML.