Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 
3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid 
leukemia (AML) patients, always predicts a poor prognosis. As a small molecule 
tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of 
advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and 
differentiated thyroid cancer (DTC), with its preclinical and clinical activity 
demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem 
duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML 
treatment, the short response duration remains a vital problem that leads to 
treatment failure. Rapid onset of drug resistance is still a thorny problem that 
we cannot overlook. Although the mechanisms of drug resistance have been studied 
extensively in the past years, there is still no consensus on the exact reason 
for resistance and without effective therapeutic regimens established 
clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant 
AML cells displayed mitochondria dysfunction, which rendered cells depending on 
glycolysis for energy supply. In my present one, we further illustrated that 
losing the target protein FLT3 and the continuously activated PI3K/Akt signaling 
pathway may be the reason for drug resistance, with sustained activation of 
PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine 
triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT 
signaling, further inhibit glycolysis to disturb ATP production, and finally 
induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD 
mutant AML patients who failed with FLT3 targeted therapy.