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1.
Mol Cancer Ther ; 6(7): 1951-61, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17620426

ABSTRACT

Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412.


Subject(s)
Antineoplastic Agents/pharmacology , Biomimetic Materials/pharmacology , Carrier Proteins , Leukemia/drug therapy , Mitochondrial Proteins , Mutant Proteins/metabolism , Oligopeptides/pharmacology , fms-Like Tyrosine Kinase 3/metabolism , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Apoptosis Regulatory Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Drug Synergism , Humans , Inhibitor of Apoptosis Proteins/metabolism , Mice , Mutant Proteins/genetics , Oligopeptides/chemistry , Staurosporine/analogs & derivatives , Staurosporine/pharmacology , Stromal Cells/drug effects , fms-Like Tyrosine Kinase 3/genetics
2.
Blood ; 109(5): 2112-20, 2007 Mar 01.
Article in English | MEDLINE | ID: mdl-17068153

ABSTRACT

Drug resistance resulting from emergence of imatinib-resistant BCR-ABL point mutations is a significant problem in advanced-stage chronic myelogenous leukemia (CML). The BCR-ABL inhibitor, nilotinib (AMN107), is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Phase 1/2 clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these 2 agents has clinical value. However, simultaneous, rather than sequential, administration of 2 BCR-ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here, we show that exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in antileukemic activity, compared with each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR-ABL kinase inhibitors is warranted.


Subject(s)
Fusion Proteins, bcr-abl/metabolism , Leukemia/drug therapy , Leukemia/metabolism , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Animals , Apoptosis/drug effects , Benzamides , Cell Line , Drug Therapy, Combination , Fusion Proteins, bcr-abl/genetics , Humans , Imatinib Mesylate , Leukemia/genetics , Leukemia/pathology , Male , Mice , Models, Biological , Phosphotyrosine/metabolism , Xenograft Model Antitumor Assays
3.
Gastroenterology ; 131(6): 1734-42, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17087936

ABSTRACT

BACKGROUND & AIMS: Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib. METHODS: The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo. RESULTS: PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA. CONCLUSIONS: Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.


Subject(s)
Gastrointestinal Stromal Tumors/genetics , Piperazines/pharmacology , Point Mutation/genetics , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Staurosporine/analogs & derivatives , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzamides , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Gastrointestinal Stromal Tumors/metabolism , Gastrointestinal Stromal Tumors/pathology , Imatinib Mesylate , Male , Mice , Mice, Nude , Phosphorylation/drug effects , Staurosporine/pharmacology , Tyrosine/metabolism , Xenograft Model Antitumor Assays
4.
Cancer Cell ; 7(2): 129-41, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15710326

ABSTRACT

The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.


Subject(s)
Antineoplastic Agents/pharmacology , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Benzamides , Bone Marrow Cells/cytology , Cell Line , Cell Line, Tumor , Cell Survival , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Hematopoietic Stem Cells/cytology , Imatinib Mesylate , Inhibitory Concentration 50 , Mice , Models, Biological , Models, Chemical , Mutation , Mycoplasma/metabolism , Phosphorylation , Piperazines/pharmacology , Retroviridae/genetics , Time Factors
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