New discovery of old drugs: new mechanism of all trans retinoic acid in flt3-itd positive leukemia

Recently, the research team of Liu Qingsong and Liu Jing, researchers of the strong magnetic field science center of the Chinese Academy of Sciences, made another progress in the new use of old drugs It was found that all trans retinoic acid (ATRA) can enhance the sensitivity of flt3-itd positive leukemia to chemotherapy drugs by down regulating the key factor CHK1 of DNA damage and repair of leukemia cells At present, this achievement is published online in the international journal Cancer Letters （ DOI: 10.1016/j.canlet.2019.12.045 ）。
Acute myeloid leukemia (AML) is a cancer of hematopoietic system caused by myeloid cell clone, proliferation and abnormal differentiation FLT3 mutation is one of the most frequent mutations in AML patients, which is about 30% - 35% Among them, FLT3 internal tandem replication (FLT3 ITD) mutations accounted for 23% - 25% of AML patients Compared with FLT3 wild-type AML, flt3-itd positive AML is easy to relapse and has poor prognosis Although small molecule drugs targeting FLT3 protein have been used in clinic, they still face the problems of low response rate and drug resistance In recent years, Liu Qingsong's pharmaceutical research team has developed a series of new inhibitors from the perspective of new drug creation At the same time, the team has also carried out a series of explorations from the perspective of new use of old drugs, hoping to meet the huge clinical diversity needs as soon as possible ATRA is an intermediate product of vitamin A metabolism in animals It plays an important role in the process of embryonic development and cell growth and differentiation by binding to its receptor rar to regulate the expression of target genes At present, ATRA is widely used as a first-line drug in the treatment of acute promyelocytic leukemia (APL) Some studies have shown that ATRA can inhibit the proliferation of flt3-itd positive leukemia cells, but its specific mechanism is not clear In this study, a large number of experiments show that ATRA can significantly down regulate the expression of CHK1 kinase, a key DNA repair factor in flt3-itd mutant acute leukemia (AML) cells, and induce the increase of leukemia DNA damage, so that ATRA can further enhance the sensitivity of DNA damage chemotherapy drugs This study provides a theoretical basis for the application of all trans retinoic acid in flt3-itd positive leukemia, and further reveals the possibility of CHK1 kinase as a target for flt3-itd positive leukemia The research results were supported by NSFC, the "personalized medicine" strategic science and technology pilot project of Chinese Academy of Sciences, the key research program of Frontier Science of Chinese Academy of Sciences, and the special support of China Postdoctoral fund.