Leukemia is a highly aggressive hematological malignancy characterized by extensive molecular changes that affect clinical outcomes and provide potential drug development targets. However, the emergence of chemotherapy resistance obviously hinders the effect of chemotherapy and indicates a poor prognosis. About 15% – 30% of leukemia patients are resistant to chemotherapy, and 60% – 80% of patients with complete remission inevitably relapse and succumb to the disease. Therefore, it is very important to evaluate chemotherapy resistance in advance for treatment decision-making and prognosis.

 

Recently, researchers published an article entitled “Targeting PI4KA sensitises chemotherapy leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis” in the journal Theranotics, which emphasized the potential of PI4KA targeted therapy to overcome the chemotherapy resistance of leukemia. The combination of PI4KA inhibitors and classical chemotherapy drugs may become a new treatment strategy for refractory leukemia.

 

 

The emergence of chemotherapy resistance in leukemia obviously hinders the effect of chemotherapy and indicates a bad prognosis. Recent evidence suggests that phosphatidylinositol 4 kinase-3 α (PI4KA) plays a key role in the occurrence and development of tumors. However, the molecular mechanism of PI4KA regulating chemoresistance and leukemia is still unclear to a large extent.

 

The researchers used liquid chromatography-mass spectrometry (LC-MS), patient samples, and a leukemia xenotransplantation mouse model to study whether PI4KA is an effective target to overcome the chemotherapy resistance of leukemia. The ELISA and molecular mechanics/generalized Born surface area (MM/GBSA) methods were used to identify cefpurine (CEP) as a new PI4KA inhibitor.

 

PI4KA is highly expressed in drug-resistant leukemia cells or relapsed leukemia patients, which is related to the low overall survival rate. PI4KA can eliminate the sensitivity of drug-resistant leukemia cells to chemotherapy drugs in vivo and in vitro by regulating ERK/AMPK/OXPHOS axis. The researchers also identified cefradine (CEP) as a new PI4KA inhibitor, which can destroy the stability of the PI4KA/TTC7/FAM126 complex and enhance the sensitivity of drug-resistant leukemia cells to chemotherapy drugs in vivo and in vitro.

 

In conclusion, the researchers revealed a new mechanism that supports the key role of PI4KA in overcoming chemoresistance in leukemia. The overexpression of PI4KA up-regulates OXPHOS by regulating the ERK/AMPK axis, leading to chemotherapy resistance of leukemia. This study emphasized the potential of PI4KA-targeted therapy to overcome the chemotherapy resistance of leukemia. The findings of this study also indicate that the combination of PI4KA inhibitors and classical chemotherapy drugs may be a new treatment strategy for refractory leukemia.

 

Reference

Xiuxing Jiang et al. Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis. Theranostics. 2022 Oct 3;12(16):6972-6988. doi: 10.7150/thno.76563.