Researchers Identify Potential AML Drug Target

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(ChemotherapyAdvisor) – A new mutation in human acute myeloid leukemia (AML) represents a valid therapeutic target, according to researchers from Pacific Biosciences and several U.S.-based research universities. The study, entitled “Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukemia,” was published online in Nature on April 15.

The researchers aimed to identify driver mutations in AML, which play a causative role in cancer, from passenger mutations, which are dispensable. Previous research studies detected activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) in approximately 20% of acute myeloid leukemia (AML) patients. Although these mutations are associated with a poor prognosis, “abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion,” the authors wrote.

In this study, however, the authors reported that there are “point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET. Also, evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220.”

The authors concluded: “Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.”


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