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Oncotarget ; 9(14): 11876-11882, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29545943


Activating KIT D816V mutations are frequently found in CBF AML, which predicts for an unfavorable outcome. Dasatinib is a potent inhibitor of wildtype and mutant-KIT isoforms - including D816V. We now provide proof of antileukemic efficacy in a patient with relapsing mutant-KIT D816V CBF AML. Importantly, this effect is mediated via overriding the differentiation blockage of the leukemia clone. In addition, we show that dasatinib is capable to induce pulmonary differentiation syndrome - and therefore needs close monitoring of patients under therapy.

PLoS One ; 8(11): e80193, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24312201


Inactivation of the p53 pathway is a universal event in human cancers and promotes tumorigenesis and resistance to chemotherapy. Inactivating p53 mutations are uncommon in non-complex karyotype leukemias, thus the p53-pathway must be inactivated by other mechanisms. The Apoptosis Stimulating Protein of p53-2 (ASPP2) is a damage-inducible p53-binding protein that enhances apoptosis at least in part through a p53-mediated pathway. We have previously shown, that ASPP2 is an independent haploinsufficient tumor suppressor in vivo. Now, we reveal that ASPP2 expression is significantly attenuated in acute myeloid and lymphoid leukemia - especially in patients with an unfavorable prognostic risk profile and patients who fail induction chemotherapy. In line, knock down of ASPP2 in expressing leukemia cell lines and native leukemic blasts attenuates damage-induced apoptosis. Furthermore, cultured blasts derived from high-risk leukemias fail to induce ASPP2 expression upon anthracycline treatment. The mechanisms of ASPP2 dysregulation are unknown. We provide evidence that attenuation of ASPP2 is caused by hypermethylation of the promoter and 5'UTR regions in native leukemia blasts. Together, our results suggest that ASPP2 contributes to the biology of leukemia and expression should be further explored as a potential prognostic and/or predictive biomarker to monitor therapy responses in acute leukemia.

Proteínas Reguladoras de Apoptose/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Adulto , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Falha de Tratamento , Resultado do Tratamento , Adulto Jovem
Cell Cycle ; 8(16): 2621-30, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19625780


AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients--predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity--resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.

Antibióticos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citarabina/farmacologia , Daunorrubicina/farmacologia , Piperazinas/farmacologia , Quinazolinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Citometria de Fluxo , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico
Mol Cancer Ther ; 8(3): 481-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19276157


Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with non-small cell lung cancer (NSCLC) that express EGFR. We recently published a phase I study of weekly matuzumab plus paclitaxel. This therapy was well tolerated and showed clinical responses in the majority of patients. Although matuzumab displays potent antitumor activity in some patients, not all patients respond well to treatment. Whether dysregulation of EGFR-mediated pathways precludes or sensitizes cells to paclitaxel is unknown. We sought to determine molecular predictive factors for therapy response in a phase I/II study patient cohort treated with matuzumab+/-paclitaxel. Twenty-three cases [including one complete response (CR), three partial responses (PR), 10 stable diseases (SD)] were screened using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), PCR/sequencing and denaturing wave high performance liquid chromatography (D-HPLC) for expression, amplification, and mutation status of EGFR and downstream signaling pathways. All patients with PR or CR displayed an either high overall or single-cell EGFR expression in the majority of cells. In addition, all of the moderate responders, who achieved SD after at least two cycles of therapy, showed diffuse EGFR expression rates and/or strong single-cell EGFR expression. In contrast, 44% of the nonresponders showed low overall or single-cell EGFR expression levels. No low-expressing EGFR cases were present within the responder group. In addition, among patients with a gain-of-function mutation in KRAS primary therapy failure and/or short responses to therapy were observed. Our data suggest that EGFR expression and KRAS mutation status is predictive for clinical response to matuzumab +/- paclitaxel in patients with advanced NSCLC.

Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes erbB-1 , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Proteínas ras/genética
Cancer Cell ; 12(6): 501-13, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18068628


Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.

Alelos , Mutação/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Animais , Proliferação de Células/efeitos dos fármacos , Análise Mutacional de DNA , Ativação Enzimática/efeitos dos fármacos , Humanos , Leucemia Monocítica Aguda/enzimologia , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patologia , Camundongos , Proteínas Mutantes/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Estrutura Secundária de Proteína , Transdução de Sinais/efeitos dos fármacos , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Tirosina Quinase 3 Semelhante a fms/química
Cancer Res ; 66(1): 473-81, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16397263


Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.

Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/enzimologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/farmacologia , Tiazóis/farmacologia , Quinases da Família src/antagonistas & inibidores , Substituição de Aminoácidos , Animais , Benzamidas , Células CHO , Processos de Crescimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Dasatinibe , Humanos , Mesilato de Imatinib , Isoenzimas/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Mutação , Fosforilação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína