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How acute myeloid leukemia(AML)escapes from FMS-related tyrosine kinase 3(FLT3)inhibitors?Still an overrated complication?

引用

Cancer Drug Resistance 2023年第2期6卷 223-238页

作者： salvatore perrone Tiziana Ottone Nadezda Zhdanovskaya Matteo Molica Hematology Polo Universitario PontinoS.M.Goretti HospitalLatina 04100Italy Department of Biomedicine and Prevention the University of Rome“Tor Vergata”Rome 00100 Italy Neuro-Oncohematology Santa Lucia FoundationI.R.C.C.S.Rome 00100Italy Hematology Department of Translational and Precision MedicineSapienza UniversityRome 00161Italy Hematology Unit S.Eugenio HospitalASL Roma 2Rome 00144Italy.

FMS-related tyrosine kinase 3(FLT3)mutations,present in about 25%-30%of acute myeloid leukemia(AML)patients,constitute one of the most frequently detected mutations in these *** binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase(PI3K)and RAS pathways,producing increased cell proliferation and the inhibition of *** types of FLT3 mutations exist:FLT3-ITD and FLT3-TKD(point mutations in D835 and I836 or deletion of codon I836).A class of drugs,tyrosine-kinase inhibitors(TKI),targeting mutated FLT3,is already available with 1st and 2nd generation molecules,but only midostaurin and gilteritinib are currently ***,the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma,as the duration of clinical responses is generally limited to a few *** review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this *** resistance been overlooked?Indeed,FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet(ELN)***,several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented:new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy,hypomethylating drugs,or IDH1/2 inhibitors,Bcl2 inhibitors;novel anti-human FLT3 monoclonal antibodies(e.g.,FLT3/CD3 bispecific antibodies);FLT3-CAR T-cells;CDK4/6 kinase inhibitor(e.g.,palbociclib).

关键词： Acute myeloid Leukemia FLT3 gilteritinib midostaurin TKI-inhibitor resistance quizartinib sorafenib crenolanib

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