Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations.
FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.
Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.
Chuanjiang
C
Yu
Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.
Rama Krishna
RK
Kancha
Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.
Justus
J
Duyster
D000595:Amino Acid Sequence; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D016415:Sequence Alignment; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C001277:geldanamycin