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1.
J Cell Mol Med ; 25(22): 10650-10662, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34708541

RESUMO

The dual-specificity tyrosine-regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence-proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi-cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER-239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure-guided drug discovery. Inhibition of DYRK1A/B by VER-239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re-expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth-promoting factors. DYRK inhibition-induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition-induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER-239353 as a treatment for glioblastoma is therefore warranted.


Assuntos
Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Glioblastoma/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/etiologia , Glioblastoma/patologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Quinases Dyrk
2.
Curr Oncol Rep ; 19(3): 19, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28251492

RESUMO

A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Apoptose/efeitos dos fármacos , Sobrevivência Celular , Humanos , Neoplasias/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/uso terapêutico , c-Mer Tirosina Quinase , Receptor Tirosina Quinase Axl
3.
EJHaem ; 3(3): 970-974, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36051036

RESUMO

Chimeric antigen receptor T cells (CAR-T) have provided promising results in multiple myeloma (MM). However, many patients still relapse, pointing toward the need of improving this therapy. Here, we analyzed peripheral blood T cells from MM patients at different stages of the disease and investigated their phenotype and capacity to generate functional CAR-T directed against CS1 or B Cell Maturation antigen. We found a decrease in naive T cells and elevated frequencies of exhaustion markers in T cells from treated MM patients. Interestingly, individuals treated with daratumumab display elevated ratios of central memory T cells. CAR-T derived from patients at relapse show reduced in vitro expansion and cytotoxic capacities in response to MM cells compared to those produced at diagnosis. Of note, CAR-T from daratumumab treated patients display intermediate defects. Reduced anti-myeloma activity of CAR T cells from treated patients was also observed in a mouse model. Our findings suggest that T cell defects in MM patients, specifically during relapse, have a major impact on their capacity to generate efficient therapeutic CAR-T. Selecting naive or central memory T cell subsets to generate therapeutic T cells could improve the CAR-T therapy for MM.

4.
Eur J Cancer ; 169: 135-145, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35567919

RESUMO

BACKGROUND: S81694 is an inhibitor of monopolar spindle 1 kinase, a target expressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients. PATIENTS AND METHODS: This trial was based on inter-individual dose-escalation of single agent S81694 in cohorts of ≥3 patients to assess the safety and tolerability and determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose (RP2D), with S81694 given on days 1,8,15 of a 28-day cycle as 1-h infusion. RESULTS: 38 patients were treated at doses ranging from 4 to 135 mg/m2/week; 144 cycles were administered (median 2/patient; range 1-32 cycles). Patients discontinued treatment for disease progression (78.9%), adverse events (AE; 18.4%) or withdrawal of consent (2.6%). Treatment modifications occurred in 22 patients (57.9%; 49 cycles). Common treatment-emergent AEs were fatigue (22 patients;57.9%), anaemia (17;44.7%) and nausea (12;31.6%). Haematological toxicity was mild, with Grade 3 anaemia observed in three patients and neutropenia mainly seen at the 135 mg/m2 dose level. Three first cycle DLTs included G3 anaemia (4 mg/m2 dose), G4 hypertension (20 mg/m2), G3 fatigue (135 mg/m2). MTD was not reached due to premature discontinuation of enrolment based on a sponsor decision. Among 35 patients evaluable for response, one (renal cell carcinoma) had a complete response, one (hepatocellular carcinoma) had a transient decrease of target lesions and 13 had stable disease. Seven patients remained on study for ≥6 cycles, two at the 135 mg/m2 dose. CONCLUSIONS: S81694 can be administered safely as a single agent in adults with solid tumours on days 1,8,15 of a 28-day cycle up to a dose of 135 mg/m2/week without reaching MTD. The RP2D was not defined due to the prioritization of the use of S81694 in combination with cytotoxic agents, based on emerging preclinical data. TRIAL REGISTRATION: EudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.


Assuntos
Anemia , Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias , Adulto , Anemia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Relação Dose-Resposta a Droga , Fadiga/etiologia , Humanos , Neoplasias Renais/tratamento farmacológico , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/etiologia
5.
CPT Pharmacometrics Syst Pharmacol ; 10(11): 1396-1411, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34708556

RESUMO

MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non-small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor-in-host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly-targeted combination therapies. The population DEB-based tumor growth inhibition (TGI) model well-described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib-resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB-TGI model allowed to capture gefitinib anticancer activity enhanced by the co-administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model-based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB-based tumor-in-host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor-in-host DEB-TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Xenoenxertos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Med Chem ; 64(10): 6745-6764, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33975430

RESUMO

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Quinases Dyrk
7.
J Med Chem ; 64(13): 8971-8991, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34143631

RESUMO

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Quinases Dyrk
8.
Methods Mol Biol ; 467: 189-210, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19301672

RESUMO

Angiogenesis is a complex sequential process involving endothelial activation, basement membrane degradation, endothelial sprouting from the parent vessel, invasion of the extracellular matrix, endothelial proliferation, vessel elongation, branching, anastomosis, increases in vessel diameter, basement membrane formation, pericyte acquisition, and remodelling. Most in vitro angiogenesis assays are two-dimensional and measure only one facet of this process, generally endothelial proliferation, migration, or tube formation. The two-dimensional nature of the assays also ignores the differences in endothelial phenotype seen in three-dimensional models and in vivo. The in vitro serum-free three-dimensional rat aortic model closely approximates the complexities of angiogenesis in vivo, from endothelial activation to pericyte acquisition and remodelling, and most of these can be quantified by image analysis, immunohistochemistry, and biochemical analysis. It is easily manipulated using molecular biological intervention or exogenous inhibitors and activators in a relatively controlled system.


Assuntos
Aorta , Técnicas de Cultura de Células/métodos , Neovascularização Fisiológica , Técnicas de Cultura de Tecidos/métodos , Animais , Aorta/citologia , Proliferação de Células , Masculino , Modelos Animais , Ratos , Ratos Endogâmicos F344
9.
Nat Commun ; 10(1): 1812, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000705

RESUMO

Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histonas/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Organofosfatos/farmacologia , Organofosfatos/uso terapêutico , Fosforilação/efeitos dos fármacos , Poliploidia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
10.
ChemMedChem ; 12(12): 932-939, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28264138

RESUMO

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.


Assuntos
Desenho de Fármacos , Harmina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Dose-Resposta a Droga , Harmina/síntese química , Harmina/química , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Dyrk
11.
Mol Cancer Ther ; 16(10): 2107-2119, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28619752

RESUMO

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR.


Assuntos
Aurora Quinase B/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Proteínas Proto-Oncogênicas c-met/genética , Aurora Quinase B/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinazolinas/administração & dosagem , Tolerância a Radiação , Receptores Proteína Tirosina Quinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl
12.
Neoplasia ; 19(1): 35-42, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27988457

RESUMO

The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/ß (PDGFRα/ß) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.


Assuntos
Amplificação de Genes , Mutação , Naftalenos/farmacologia , Quinolinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Dosagem de Genes , Humanos , Concentração Inibidora 50 , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Mol Cancer Ther ; 12(9): 1749-62, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23804704

RESUMO

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Indóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Bevacizumab , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/química , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tiazolidinedionas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl
14.
Sci Signal ; 2(102): er11, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20039471

RESUMO

Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. In some cases, however, cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependence results in tumor regression upon oncogene inactivation ("oncogene addiction"). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this response to oncogene neutralization is crucial to identifying the vulnerabilities of cancer. Using the Met receptor as the major model system, we combined multiplex phosphoproteomics, genome-wide expression profiling, and functional assays in various cancer cells addicted to oncogenic receptor tyrosine kinases. We found that Met blockade affected a limited subset of Met downstream signals: Little or no effect was observed for several pathways downstream of Met; instead, only a restricted and pathway-specific signature of transducers and transcriptional effectors downstream of Ras or phosphoinositide 3-kinase (PI3K) was inactivated. An analogous signature was also generated by inhibition of epidermal growth factor receptor in a different cellular context, suggesting a stereotyped response that likely is independent of receptor type or tissue origin. Biologically, Met inhibition led to cell-cycle arrest. Inhibition of Ras-dependent signals and PI3K-dependent signals also resulted in cell-cycle arrest, whereas cells in which Met was inhibited proliferated when Ras or PI3K signaling was active. These findings uncover "dominant" and "recessive" nodes among the numerous oncogenic networks regulated by receptor tyrosine kinases and active in cancer, with the Ras and PI3K pathways as determinants of therapeutic response.


Assuntos
Ciclo Celular/fisiologia , Inativação Gênica/fisiologia , Neoplasias/metabolismo , Oncogenes/fisiologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/fisiologia , Western Blotting , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Perfilação da Expressão Gênica , Proteínas de Fluorescência Verde/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Oncogênica p21(ras)/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Reação em Cadeia da Polimerase , Proteômica , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/genética , Análise de Sequência de DNA
15.
Sci Signal ; 2(100): ra80, 2009 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-19996456

RESUMO

Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. In some cases, however, cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependence results in tumor regression upon oncogene inactivation ("oncogene addiction"). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this response to oncogene neutralization is crucial to identifying the vulnerabilities of cancer. Using the Met receptor as the major model system, we combined multiplex phosphoproteomics, genome-wide expression profiling, and functional assays in various cancer cells addicted to oncogenic receptor tyrosine kinases. We found that Met blockade affected a limited subset of Met downstream signals: Little or no effect was observed for several pathways downstream of Met; instead, only a restricted and pathway-specific signature of transducers and transcriptional effectors downstream of Ras or phosphoinositide 3-kinase (PI3K) was inactivated. An analogous signature was also generated by inhibition of epidermal growth factor receptor in a different cellular context, suggesting a stereotyped response that likely is independent of receptor type or tissue origin. Biologically, Met inhibition led to cell-cycle arrest. Inhibition of Ras-dependent signals and PI3K-dependent signals also resulted in cell-cycle arrest, whereas cells in which Met was inhibited proliferated when Ras or PI3K signaling was active. These findings uncover "dominant" and "recessive" nodes among the numerous oncogenic networks regulated by receptor tyrosine kinases and active in cancer, with the Ras and PI3K pathways as determinants of therapeutic response.


Assuntos
Oncogenes , Proteínas Proto-Oncogênicas c-met/metabolismo , Western Blotting , Linhagem Celular , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Oncogênica p21(ras)/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais
17.
Mol Pharmacol ; 63(6): 1281-8, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12761337

RESUMO

The role of adhesion molecules, such as alphav integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule alphav integrin antagonist, to investigate the role of integrin-signaling in the survival of populations of quiescent human HT-29 and HCT 116 colon carcinoma cells. S 34961 at 1 microM induced detachment, but cells retained viability, existing as clusters. Nonligated beta-integrins may recruit and activate caspase-8 [J Cell Biol 155:459-470, 2001]. However, congruent with the absence of apoptosis, no activation of caspase-8 in these cells was detected after incubation with S 34961. A rapid (2 h) change in conformation of the N terminus of proapoptotic Bak was observed before detachment, together with a decrease in phosphorylation of focal adhesion kinase (2 h) and subsequent (8 h) decreases in phosphorylation of extracellular signal-regulated kinase-1/2 and Akt. Together, these results suggested that although treatment with S 34961 has no effect on survival per se, it may reduce the survival threshold of the tumor cells, with Bak in an activated state. Indeed, concomitant incubation of S 34961 with 10 microM U-0126 (a mitogen-activated protein kinase kinase inhibitor) was found to lead to apoptosis (at 24 h), whereas U-0126 alone had no effect. Together, these observations could guide the use of combination therapy with integrin antagonists in the clinic.


Assuntos
Caspases/metabolismo , Neoplasias do Colo/patologia , Cicloeptanos/farmacologia , Integrina alfa5/metabolismo , Integrinas/antagonistas & inibidores , Piridinas/farmacologia , Apoptose , Caspase 8 , Caspase 9 , Adesão Celular , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Ativação Enzimática , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Células HT29 , Humanos , Integrina alfa5/efeitos dos fármacos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2
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