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1.
Adv Exp Med Biol ; 1252: 115-124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32816270

RESUMO

Available data on systemic treatments in pregnancy-associated breast cancer (PABC) is reviewed in this section. These treatments include chemotherapy, endocrine therapy (ET), small molecule inhibitors, monoclonal antibodies against human epidermal growth factor receptor 2 (EGFR-2) also known as HER2; and human epidermal growth factor receptor 3 (EGFR-3), also known as HER3.In local disease, systemic treatment can be delivered as neoadjuvant (before surgery) or adjuvant (after surgery) treatment. In metastatic disease, systemic therapy is the main modality of treatment.Approach to PABC is based on available data in the general population, limited only by safety issues for use of medications during gestation and lactation. Therefore, treatments are similar to non-PABC patients while trying to minimize the risk to the fetus. Available data on different chemotherapies, anti-HER2 monoclonal antibodies, ET and small molecule inhibitors are discussed in detail.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Terapia Neoadjuvante , Metástase Neoplásica/tratamento farmacológico , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
2.
Anticancer Res ; 40(6): 3315-3323, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487627

RESUMO

BACKGROUND/AIM: To evaluate the improvement in the prognosis by adjuvant trastuzumab in clinical practice and the risk factors for distant recurrence, we retrospectively investigated the prognosis of HER2-positive early breast cancer in our department before and after the introduction of adjuvant trastuzumab. PATIENTS AND METHODS: Cohorts A and B included 161 and 182 cases, respectively, who underwent surgery before (2000-2007) and after (2008-2015) the introduction of adjuvant trastuzumab. RESULTS: The rates of relapse-free and distant metastasis-free survival were significantly better in cohort B than in cohort A. The risk factors of distant recurrence found in cohort A, such as the presence of lymph node metastasis, lymphatic invasion, and a low histological grade, did not increase the risk in cohort B. CONCLUSION: Many risk factors seemed to have been negated by adjuvant trastuzumab administration. Therefore, further escalation of adjuvant treatment should be carefully considered.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Estudos Retrospectivos , Análise de Sobrevida , Trastuzumab/farmacologia
3.
PLoS One ; 15(6): e0234146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525891

RESUMO

Approximately 20% of breast cancers are HER2-positive. Trastuzumab has improved patient outcomes significantly for these cancers. However, acquired resistance remains a major hurdle in the clinical management of these patients. Therefore, identifying molecular changes that cause trastuzumab resistance is worthwhile. STAT6 is a transcription factor that regulates a variety of genes involved in cell cycle regulation, growth inhibition, and apoptosis. STAT6 expression is lost in approximately 3% of breast cancers, but little work has been done in the context of trastuzumab resistance in breast cancer. In isogenic cell line pairs, we observed that trastuzumab-resistant cells expressed significantly lower levels of STAT6 compared to trastuzumab-sensitive cells. Therefore, in order to study the consequences of STAT6 loss in HER2+ breast cancer, we knocked out both alleles of the STAT6 gene using somatic cell gene targeting. Interestingly, loss of STAT6 resulted in anchorage-independent growth and changes in several genes involved in epithelial to mesenchymal transition. This study suggests that STAT6 may play a role in the pathophysiology of HER2+ human breast cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Fator de Transcrição STAT6/genética , Trastuzumab/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , RNA Guia/metabolismo , Receptor ErbB-2/genética , Fator de Transcrição STAT6/deficiência
4.
PLoS One ; 15(6): e0234991, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584853

RESUMO

The breast cancer (BC) biomarker HER2 (Human Epidermal Receptor 2) is overexpressed in 25% of BC. Only patients with HER2-positive tumors receive HER2-targeting therapies, like trastuzumab (Herceptin). However, some women with a HER2-negative BC could benefit from trastuzumab. This could be explained by the activation/phosphorylation of HER2 that can be recognized by trastuzumab. The aim of this study is to examine trastuzumab effects on HER2 phosphorylation at tyrosine Y877 (pHER2Y877). HER2 and pHER2Y877 status were evaluated in a cohort of BC patients representative of molecular subtypes distribution (n = 497) and in a series of BC cell lines (n = 7). Immunohistochemistry against pHER2Y877 was performed on tissue micro arrays. Cellular proliferation assays were performed on BC cell lines presenting different combinations of HER2 and pHER2Y877 status and treated with increasing doses of trastuzumab (0-150 µg/ml). The prevalence of pHER2Y877 in this cohort was 6%. Nearly 5% of patients with HER2-negative tumors (n = 406, 82%) overexpressed pHER2Y877. Among triple negative BC patients (n = 39, 8%), 7.7% expressed pHER2Y877. Trastuzumab treatment decreased cell proliferation in HER2-/pHER2Y877+ BC cell lines, to an extent comparable to what occurs in HER2+ cell lines, but did not affect HER2-/pHER2Y877- cell lines. Trastuzumab sensitivity in HER2-/pHER2Y877+ cell line is specific to HER2 tyrosine 877 phosphorylation. Hence, with further confirmation in a bigger cohort, trastuzumab treatment could be envisaged as a treatment option to women presenting with HER2-/pHER2+ tumors, representing more than 1000 BC women in Canada in 2019.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Neoplasias da Mama/patologia , Canadá , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fosforilação , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Análise Serial de Tecidos , Trastuzumab/uso terapêutico , Tirosina/metabolismo
5.
Anticancer Res ; 40(4): 1921-1930, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234881

RESUMO

BACKGROUND/AIM: Targeting of the human epidermal growth factor receptor 2 (HER2) is suggested to be beneficial for esophageal squamous cell carcinoma (ESCC) patients with HER2 amplification. In this study, we evaluated the effects of combination chemotherapy with HER2-targeted drug trastuzumab in ESCC cells and examined the underlying mechanism contributing to these effects. MATERIALS AND METHODS: HER2 expression was verified, and the efficacy of chemotherapy with and without trastuzumab was investigated in vitro and in vivo. RESULTS: The combination of trastuzumab and a combined-modality therapy stimulated the PI3K/Akt pathway in ESCC cells overexpressing HER2. Trastuzumab treatment resulted in the intranuclear accumulation of FOXO3A in ESCC xenografts overexpressing HER2. The combination of trastuzumab and a combined-modality therapy enhanced antitumor effects in HER2-overexpressing ESCC xenografts. CONCLUSION: FOXO3A plays an important role in mediating the effects of trastuzumab, and combination chemotherapy may be a promising treatment for patients with HER2-overexpressing ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Proteína Forkhead Box O3/genética , Receptor ErbB-2/genética , Trastuzumab/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética
6.
Cancer Sci ; 111(6): 2123-2131, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248641

RESUMO

HER2-targeting antibodies (trastuzumab, pertuzumab) and a HER2-directed antibody-drug conjugate (trastuzumab emtansine: T-DM1) are used for the treatment of HER2-overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small-molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T-DM1 for evaluating the effect of TAS0728 on HER2 antibody-resistant populations. Treatment with trastuzumab and pertuzumab or with T-DM1 initially induced tumor regression in NCI-N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T-DM1, HER2-HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti-tumor effect associated with HER2-HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient-derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T-DM1, TAS0728 exerted a potent anti-tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T-DM1 are still dependent on oncogenic HER2-HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti-HER2 therapies.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Ado-Trastuzumab Emtansina/farmacologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Pathol ; 251(2): 187-199, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32237123

RESUMO

Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2-targeted therapy has given rise to disappointing results in non-small cell lung cancer (NSCLC). With the aim of refining the target population for anti-HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti-HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT-silenced tumour cell lines. Finally, we showed that the FHITlow /pHER2high phenotype predicts sensitivity to an anti-HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT-inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti-HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Hidrolases Anidrido Ácido/metabolismo , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/farmacologia , Células A549 , Hidrolases Anidrido Ácido/genética , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Steroid Biochem Mol Biol ; 200: 105651, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32147458

RESUMO

Target-specific transport of therapeutic agents holds promise to increase the efficacy of cancer treatment by decreasing injury to normal tissues and post treatment problems. HER2 is a tumor cell surface marker that is expressed in 25-30 % of breast cancer patients. The significant role of HER2 in cancer development and its biological feature makes it a highly appealing goal for the therapeutic treatment of cancer targeted therapy using HER2 monoclonal antibody. This approach is currently used as a special treatment against breast cancer in some research. In the present study, HER2 monoclonal antibody (mAb), (Herceptin) fused to PE38 by recombinant DNA technology and a new recombinant IT was developed. The scFv(Herceptin)-PE-STXA and scFv(Herceptin)-PE fusions cloned in pET28a and recombinant protein expression was carried out and then the proteins were purified. MCF-7 and SKBR-3 cells were used as HER2-negative and HER2-positive breast cancer cells, respectively. The cytotoxicity of its evaluated using MTT assay. The cell ELISA was used to determine the binding ability of immunotoxins (ITs) to the cell receptor and internalization and apoptosis were also assessed. The results revealed that cell cytotoxicity occurred in SKBR-3 cells in a dose-dependent manner but not in MCF-7 cells. It is possible that this ITs can attach to HER2-positive breast cancer cells and then, internalize and eradicate cancer cells by apoptosis. Here, we concluded that the recombinant ITs have therapeutic potential against HER2-positive breast cancer.


Assuntos
ADP Ribose Transferases , Antineoplásicos Imunológicos/farmacologia , Toxinas Bacterianas , Neoplasias da Mama/tratamento farmacológico , Exotoxinas , Imunotoxinas/farmacologia , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Trastuzumab/farmacologia , Fatores de Virulência , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
9.
BMC Cancer ; 20(1): 235, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32192443

RESUMO

BACKGROUND: The relationship of neutrophil/lymphocyte ratio (NLR) to prognosis of HER2-positive breast cancer (BC) is not well studied. We aimed to assess the prognostic role of NLR in HER2-positive BC patients treated with or without trastuzumab. METHODS: The clinical data of 843 HER2-positive BC patients from July 2013 to July 2018 were collected. The difference among variables was calculated by chi-square test. The associations between clinicopathological factors, NLR and disease-free survival (DFS) were analyzed by univariate and multivariate analyses. RESULTS: Patients were divided into three groups. In group 1 containing 255 patients without trastuzumab treatment, pretreatment NLR showed no predictive value. Patients with trastuzumab treatment were divided into two groups on equal, according to pretreatment NLR values, low NLR (group 2) and high NLR (group 3). Patients in group 2 showed significantly higher 3-year DFS rate than patients in group 1 and group 3 (95.3% vs. 91.6% vs. 90.5%, respectively, P = 0.011); patients in the group 1 and group 3 had a similar 3-year DFS outcome. Multivariate analysis showed high pretreatment NLR was significantly associated with shorter DFS (HR = 2.917, 95% CI = 1.055-8.062, P = 0.039) in HER2-positive BC patients treated with trastuzumab. CONCLUSIONS: Among HER2-positive trastuzumab-treated BC patients, low pretreatment NLR value was associated with better DFS, and it might help to differentiate potential beneficiaries of trastuzumab treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neutrófilos/citologia , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Contagem de Linfócitos , Análise Multivariada , Neutrófilos/efeitos dos fármacos , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Trastuzumab/farmacologia , Resultado do Tratamento
10.
Cancer Biother Radiopharm ; 35(3): 177-189, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32196365

RESUMO

Background: Human epidermal growth factor receptor 2 (HER2) is found to be amplified in ∼15%-20% of breast cancers. In this study, the authors report the synthesis and comparative in vitro therapeutic efficacy of 177Lu-CHX-A″-DTPA-trastuzumab and 177Lu-CHX-A″-DTPA-F(ab')2-trastuzumab to determine their potential as theranostic agents for patients with breast cancer. Materials and Methods: Bivalent F(ab')2-trastuzumab was produced by enzymatic digestion of trastuzumab, conjugated with p-SCN-Bn-CHX-A″-DTPA and subsequently radiolabeled with 177Lu. Cell viability, membrane toxicity assays, and apoptosis analysis were carried out with 177Lu-CHX-A″-DTPA-trastuzumab and 177Lu-CHX-A″-DTPA-F(ab')2-trastuzumab in HER2-positive ovarian (SK-OV-3) and breast cancer (SK-BR-3 and MDA-MB-453) cells. Results: In vitro cell binding studies showed ∼20%-25% binding of 177Lu-CHX-A″-DTPA-trastuzumab and 177Lu-CHX-A″-DTPA-F(ab')2-trastuzumab to SK-OV-3, SK-BR-3, and MDA-MB-453 cells. The cells exhibited similar degree of membrane integrity and cellular toxicity when treated with same amount (activity) of 177Lu-CHX-A″-DTPA-F(ab')2-trastuzumab and 177Lu-CHX-A″-DTPA-trastuzumab, and the toxicity was dose dependent. The mode of cell death was predominantly by apoptosis and necrosis with both the radioimmunoconjugates. Conclusions: The results indicated that the efficacy of both the radioimmunoconjugates, in terms of inducing cell death, was similar thereby ascertaining their potential as good therapeutic agents for patients with breast cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Humanos , Trastuzumab/farmacologia
11.
Cell ; 180(5): 895-914.e27, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142680

RESUMO

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias/tratamento farmacológico , Proclorperazina/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Apresentação do Antígeno/efeitos dos fármacos , Biópsia , Cetuximab/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Endocitose/efeitos dos fármacos , Endocitose/imunologia , Xenoenxertos , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células MCF-7 , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Trastuzumab/farmacologia
12.
Heart Fail Clin ; 16(2): 231-241, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32143767

RESUMO

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.


Assuntos
Antraciclinas/farmacologia , Insuficiência Cardíaca , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias/tratamento farmacológico , Trastuzumab/farmacologia , Antineoplásicos/farmacologia , Cardiotoxicidade , Monitoramento de Medicamentos/métodos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos
13.
Oncogene ; 39(14): 3028-3040, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32042115

RESUMO

The proviral integration of Moloney virus (PIM) family of protein kinases are overexpressed in many haematological and solid tumours. PIM kinase expression is elevated in PI3K inhibitor-treated breast cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast cancer, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both PIM and PI3K/AKT/mTOR signalling. We thus evaluated the preclinical activity of IBL-302, in a range of breast cancer models. Our results demonstrate in vitro efficacy of IBL-302 in a range of breast cancer cell lines, including lines with acquired resistance to trastuzumab and lapatinib. IBL-302 demonstrated single-agent, anti-tumour efficacy in suppression of pAKT, pmTOR and pBAD in the SKBR-3, BT-474 and HCC-1954 HER2+/PIK3CA-mutated cell lines. We have also shown the in vivo single-agent efficacy of IBL-302 in the subcutaneous BT-474 and HCC-1954 xenograft model in BALB/c nude mice. The combination of trastuzumab and IBL-302 significantly increased the anti-proliferative effect in HER2+ breast cancer cell line, and matched trastuzumab-resistant line, relative to testing either drug alone. We thus believe that the novel PIM and PI3K/mTOR inhibitor, IBL-302, represents an exciting new potential treatment option for breast cancer, and that it should be considered for clinical investigation.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tiofenos/farmacologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lapatinib/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Trastuzumab/farmacologia
14.
Sci Rep ; 10(1): 2986, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076029

RESUMO

HER2 overexpression is frequently associated with tumor metastasis and poor prognosis of breast cancer. More evidence indicates that HER3 is involved in HER2-resistant therapies. Combination treatments with two or more different monoclonal antibodies are a promising strategy to overcome resistance to HER2 therapies. We presented a novel fully human HER2-targeted monoclonal antibody, GB235, screened from a phage-display library against the HER2 antigen. GB235 in combination with Trastuzumab overcomes resistance in HER2-positive tumors and results in more sustained inhibition of tumor growth over time. The competition binding assay showed that the epitopes of GB235 do not overlap with those of Pertuzumab and Trastuzumab on HER2. Further HER2 mutagenesis results revealed that the binding epitopes of GB235 were located in the domain III of HER2. The mechanism of action of GB235 in blocking HER2-driven tumors is different from the mechanisms of Trastuzumab or Pertuzumab. GB235 does not affect the heterodimerization of HER2 and HER3, whereas the GB235 combined treatment with Trastuzumab significantly inhibited heregulin-induced HER3 phosphorylation and downstream signaling. Moreover, GB235 in combination with Trastuzumab reversed the resistance to heregulin-induced proliferation in HER2-overexpressing cancer cell lines. GB235 combined with Trastuzumab treatment in xenograft models resulted in improved antitumor activity. Complete tumor suppression was observed in the HER2-positive NCI-N87 xenograft model treated with the combination treatment with GB235 and Trastuzumab. In a Trastuzumab-resistant patient-derived tumor xenograft model GA0060, GB235 plus Trastuzumab reversed the resistance to Trastuzumab monotherapy. Because GB235 showed a different working mechanism with Pertuzumab and Trastuzumab, these agents can be considered complementary therapy against HER2 overexpression tumors.


Assuntos
Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Neoplasias/patologia , Neuregulina-1/metabolismo , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Immunother Cancer ; 8(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940587

RESUMO

BACKGROUND: The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized. METHODS: We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach. RESULTS: VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the "do not eat me" signal CD47 on tumor cells. CONCLUSIONS: HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/farmacologia , Ácido Valproico/farmacologia , Vorinostat/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacologia , Humanos , Fagocitose/efeitos dos fármacos , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Receptores de IgG/metabolismo , Trastuzumab/administração & dosagem , Ácido Valproico/administração & dosagem , Vorinostat/administração & dosagem
16.
Nat Commun ; 11(1): 385, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959756

RESUMO

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Mama/patologia , Receptor ErbB-2/metabolismo , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Biópsia , Mama/efeitos dos fármacos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Terapia Neoadjuvante/métodos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento
18.
Cancer Lett ; 472: 119-131, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31866466

RESUMO

Although trastuzumab has greatly improved the outcome of HER2-positive breast cancer, the emergence of resistance hampers its clinical benefits. Trastuzumab resistance is a multi-factorial consequence predominantly due to presence of cancer stem-like cells (CSCs). AZD1775, a potent anti-cancer agent targeting WEE1 kinase to drive tumor cells with DNA damage to premature mitosis, has previously shown high efficacies when targeting different cancers with a well-tolerated cytotoxic profile, but has not been evaluated in trastuzumab-resistant (TrR) breast cancer. We sought to investigate the effect of AZD1775 on cancer stem-like cell (CSC) properties, apoptosis, cell cycle regulation in TrR breast cancer. Our study for the first time demonstrated that AZD1775 induces apoptosis and arrests TrR cells at G2/M phase. More importantly, AZD1775 effectively targeted CSC properties by suppressing MUC1 expression levels. AZD1775 administration also induced apoptosis in our in-house patient-derived tumor cell line at passage 0, implying its significant clinical relevance. These findings highlight the potential clinical application of AZD1775 in overcoming trastuzumab resistance in breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Proteínas Tirosina Quinases/genética , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Trastuzumab/farmacologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Xenoenxertos , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/genética
19.
Sci Rep ; 9(1): 19881, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882666

RESUMO

This study aimed to investigate the roles and possible molecular mechanisms of long non-coding RNA HOTAIR in regulating resistance to trastuzumab in breast cancer. Trastuzumab-resistant breast cancer cell line SK-BR-3-TR was assayed for the expression of HOX antisense intergenic RNA (HOTAIR), epithelial-mesenchymal transition (EMT)-related proteins or genes. Methylation levels of TGF- ß, PTEN and cyclin-dependent kinase inhibitor 1B (or P27) were determined. In trastuzumab-resistant cell line, the mRNA level of HOTAIR was significantly up-regulated; in addition, the expression of TGF-ß, Snail and Vimentin was also up-regulated, E-cadherin was down-regulated while the expression of HER2, PI3K, AKT, mTOR and MAPK in the HER2 receptor pathway and phosphorylation level of HER2 receptor remained unchanged, the methylation levels of the PTEN gene and TGF-ß were increased and decreased, respectively. RNA interference downregulated the HOTAIR level and sensitized the cells to trastuzumab. It also resulted in down-regulation of TGF-ß, Snail, Vimentin, p-AKT, p-APK and CyclinD1 and up-regulation of E-cadherin, PTEN and P27. Besides, the methylation levels of the PTEN gene and TGF-ß were reduced and increased, respectively. Mouse models grafted with SK-BR-3-TR grew faster than with SK-BR-3-TS and siHOTAIR-SK-BR-3-TR.


Assuntos
Neoplasias da Mama/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
IET Nanobiotechnol ; 13(8): 808-815, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31625520

RESUMO

Breast cancer is the second cause of death in the world. Ionising radiation is a potent mutagen that can cause DNA damage, chromosomes breakage, and cell death. In the present study, radiotherapy and nanoparticle-antibodies (ABs) have been combined to enhance the efficacy of cancer cell treatment. Silver nanoparticles (SNP) were synthesised, coated with anti-HER2, and then characterised with different techniques such as X-ray diffraction, dynamic light scattering, transmission electron microscopy, Fourier transform infrared, and UV-Vis spectroscopy. SKBR3 cells were irradiated with cobalt-60 in the presence of nanoparticle-AB as the drug. Cell viability was measured using the diphenyltetrazolium bromide assay, and the cellular status was assessed by Raman spectroscopy. Irradiation considerably decreased cell viability proportionate to the dose increase and post-irradiation time. The surface-enhanced Raman spectroscopy increased the signal in the presence of SNP. Increasing the dose to 2 Gy increased the irradiation resistance, and higher dose increases (4 and 6 Gy) enhanced the irradiation sensitivity. Moreover, the cellular changes induced by irradiation in the presence of the drug were stable after 48 h. The authors results introduced the combination of the drug with radiation as an effective treatment for cancer and Raman spectroscopy as a suitable tool to diagnose effective irradiation doses.


Assuntos
Neoplasias da Mama/radioterapia , Materiais Revestidos Biocompatíveis/farmacologia , Nanopartículas Metálicas/química , Tolerância a Radiação/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Prata/química , Trastuzumab/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Materiais Revestidos Biocompatíveis/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Difusão Dinâmica da Luz , Feminino , Raios gama/uso terapêutico , Humanos , Teste de Materiais , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Prata/farmacologia , Análise Espectral Raman , Trastuzumab/química , Trastuzumab/uso terapêutico , Difração de Raios X
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