A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML.
Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the beta-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)-induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs.
Breitenbuecher
Frank
F
3rd Medical Department, Johannes Gutenberg-University, Mainz, Germany.
Markova
Boyka
B
Kasper
Stefan
S
Carius
Birgit
B
Stauder
Torsten
T
Böhmer
Frank D
FD
Masson
Kristina
K
Rönnstrand
Lars
L
Huber
Christoph
C
Kindler
Thomas
T
Fischer
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D040081:Protein Array Analysis; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013379:Substrate Specificity; D015854:Up-Regulation / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019311:Staurosporine; C059539:midostaurin