Huang Amin, Zeng Peiting, Li Yinguang, Lu Wenhua, Lai Yaoming
Department of Medical Oncology of the East Division, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Front Oncol. 2021 Nov 8;11:782065. doi: 10.3389/fonc.2021.782065. eCollection 2021.
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.
FMS样酪氨酸激酶3（FLT3）内部串联重复（ITD）突变是急性髓系白血病（AML）患者中最常见的突变，发生率近20%，常预示预后不良。索拉非尼作为一种小分子酪氨酸激酶抑制剂，临床上用于治疗晚期肾细胞癌（RCC）、肝细胞癌（HCC）和分化型甲状腺癌（DTC），其在治疗Fms样酪氨酸激酶3内部串联重复（FLT3-ITD）突变型AML中的临床前和临床活性已得到证实。尽管它在AML治疗中显示出光明的前景，但短反应持续时间仍然是导致治疗失败的关键问题。耐药性的快速出现仍然是一个我们不能忽视的棘手问题。尽管过去几年对耐药机制进行了广泛研究，但对于耐药的确切原因仍未达成共识，临床上也未建立有效的治疗方案。我之前的工作报道，对索拉非尼耐药的FLT3-ITD突变型AML细胞表现出线粒体功能障碍，这使得细胞依赖糖酵解来提供能量。在我目前的研究中，我们进一步阐明，失去靶蛋白FLT3和持续激活的PI3K/Akt信号通路可能是耐药的原因，PI3K/AKT信号通路的持续激活导致了高糖酵解活性和三磷酸腺苷（ATP）生成。PI3K抑制剂LY294002可以阻断PI3K/AKT信号通路，进一步抑制糖酵解以干扰ATP生成，最终诱导细胞凋亡。这一发现将为治疗FLT3靶向治疗失败的FLT3-ITD突变型AML患者铺平道路。
