Smac mimetics: implications for enhancement of targeted therapies in leukemia.
Drug resistance is a growing concern with clinical use of tyrosine kinase inhibitors. Utilizing in vitro models of intrinsic drug resistance and stromal-mediated chemoresistance, as well as functional mouse models of progressive and residual disease, we attempted to develop a potential therapeutic approach designed to suppress leukemia recurrence following treatment with selective kinase inhibitors. The novel IAP inhibitor, LCL161, [corrected] was observed to potentiate the effects of tyrosine kinase inhibition against leukemic disease both in the absence and presence of a stromal-protected [corrected] environment. LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. In addition, LCL161 synergized in vivo with nilotinib to reduce leukemia burden significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib. Finally, LCL161 displayed antiproliferative effects against cells characterized by intrinsic resistance to tyrosine kinase inhibitors as a result of expression of point mutations in the protein targets of drug inhibition. These results support the idea of using IAP inhibitors in conjunction with targeted tyrosine kinase inhibition to override drug resistance and suppress or eradicate residual disease.
Weisberg
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E
Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA 02115, USA. Ellen_Weisberg@dfci.harvard.edu
Ray
A
A
Barrett
R
R
Nelson
E
E
Christie
A L
AL
Porter
D
D
Straub
C
C
Zawel
L
L
Daley
J F
JF
Lazo-Kallanian
S
S
Stone
R
R
Galinsky
I
I
Frank
D
D
Kung
A L
AL
Griffin
J D
JD
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib; D019311:Staurosporine; C059539:midostaurin