Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.126
Filtrar
1.
Medicine (Baltimore) ; 100(6): e24688, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578601

RESUMO

RATIONALE: The incidence of nonsmall cell lung cancer (NSCLC) is high. Most nonsmall cell lung cancers have undergone multiple metastases at the time of initial diagnosis, and the 5 year survival rate is low. At present, comprehensive treatments, including systemic chemotherapy, targeted therapy, antiangiogenic therapy, and immunotherapy, prolong the survival of patients with advanced NSCLC. Herein, we report a case of NSCLC with long-term survival. PATIENT CONCERNS: A 61-year-old woman complained of dry cough and shortness of breath and visited our hospital in July 2011. Imaging examination revealed a left upper lung mass with multiple metastases to the liver, adrenal gland, and bone. DIAGNOSES: Stage IVB (cT2aN3M1c) lung adenocarcinoma was diagnosed, with multiple metastases of the lymph nodes, liver, adrenal gland, and bone. INTERVENTIONS AND OUTCOMES: The patient received systemic chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor-targeted therapy, and has survived for more than 9 years. LESSONS: The patient benefited from maintenance chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor treatment and achieved long-term survival.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/secundário , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Quimioterapia de Manutenção/métodos , Adenocarcinoma de Pulmão/diagnóstico por imagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Sobreviventes , Tomografia Computadorizada por Raios X/métodos
2.
Life Sci ; 266: 118886, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310044

RESUMO

AIMS: Triple negative breast cancer (TNBC) has drawn more and more attention due to its high mitotic indices, high metastatic rate and poor prognosis. Gene therapy, especially RNA interference (RNAi), has become a promising targeted therapy. However, improvement of transfection efficiency and discovery of target genes are major problems for the delivery of small interfering RNAs (siRNA). MATERIALS AND METHODS: In the present study, we developed GALA- and CREKA-modified PEG-SS-PEI to deliver siRNAs targeting on EGFR and BRD4 for TNBC therapy. The PEG-SS-PEI/siRNA complexes were prepared by electrostatic interaction and characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). The release characteristic, stability, cellular uptake and intracellular localization of the complexes were also studied. The effect of the complexes on cell viability was measured in MDA-MB-231 and HUVEC cells. The in vitro anti-tumor activities of the complexes were analyzed by Transwell invasion assay and wound healing assay. The gene silencing effect was evaluated by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. KEY FINDINGS: The results revealed that the GALA- and CREKA-modified PEG-SS-PEI/siRNA complexes showed excellent transfection efficiency with redox-sensitive release profile and good biological compatibility. The complexes protected siRNA from the degradation of RNA enzymes. The complexes significantly inhibited the proliferation, invasion and migration of MDA-MB-231 cells via the synergistic inhibition of EGFR/PI3K/Akt and BRD4/c-Myc pathways. SIGNIFICANCE: Taken together, co-delivery of siEGFR and siBRD4 by GALA-PEG-SS-PEI and CREKA-PEG-SS-PEI may provide a more effective strategy for the treatment of TNBC.


Assuntos
Proteínas de Ciclo Celular/administração & dosagem , Peptídeos Penetradores de Células/química , Inativação Gênica , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , RNA Interferente Pequeno/administração & dosagem , Fatores de Transcrição/administração & dosagem , Neoplasias de Mama Triplo Negativas/terapia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proliferação de Células , Receptores ErbB/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Terapia Genética , Humanos , Polietilenoimina/química , RNA Interferente Pequeno/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
3.
N Z Med J ; 133(1527): 83-94, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33332330

RESUMO

AIM: Drug-induced ocular inflammation is rare and may be overlooked as a cause of uveitis. The main objective was to describe the causes of drug-induced ocular inflammation. Secondary objectives included uveitis complications and drug rechallenge reactions. METHODS: A retrospective chart review at Auckland District Health Board's tertiary uveitis clinic (Auckland, New Zealand) was performed. Participants were identified using the uveitis database, which consists of 2,750 subjects. Fifty eyes of 35 subjects had drug-induced inflammation. RESULTS: Drug-induced inflammation occurred in 1.3% of subjects with uveitis. Mean age was 66.8±15.6 years, and 25 subjects (71.4%) were female. Drugs responsible were bisphosphonates (24 subjects, 68.6%), brimonidine (one subject, 2.9%), etanercept (three subjects, 8.6%), immune checkpoint inhibitors (two subjects, 5.7%), BRAF inhibitors (three subjects, 8.6%), EGFR inhibitors (one subject, 2.9%) and allopurinol/perindopril (one subject, 2.9%). In subjects with bisphosphonate inflammation, anterior uveitis occurred in 22 (91.7%) and scleritis in two (8.3%). A positive rechallenge reaction occurred in two subjects with zoledronate and one with alendronate. Uveitis occurred in six subjects (17.1%) treated with cancer drugs including immune checkpoint inhibitors, BRAF inhibitors and EGFR protein kinase inhibitors. Subjects with cancer-drug-induced uveitis were managed with corticosteroids and five subjects were able to continue therapy; in one subject uveitis was uncontrollable and required drug cessation. CONCLUSIONS: Ocular inflammation caused by bisphosphonates is usually mild and resolves on medication withdrawal. Uveitis seen in association with newer cancer medications can be more severe, but in most cases it can be managed without medication cessation.


Assuntos
Difosfonatos/efeitos adversos , Uveíte Anterior/induzido quimicamente , Ácido Zoledrônico/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Alopurinol/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Tartarato de Brimonidina/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Etanercepte/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Esclerite/induzido quimicamente , Vemurafenib/efeitos adversos
4.
BMC Bioinformatics ; 21(1): 520, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33183223

RESUMO

BACKGROUND: Protein kinases are a large family of druggable proteins that are genomically and proteomically altered in many human cancers. Kinase-targeted drugs are emerging as promising avenues for personalized medicine because of the differential response shown by altered kinases to drug treatment in patients and cell-based assays. However, an incomplete understanding of the relationships connecting genome, proteome and drug sensitivity profiles present a major bottleneck in targeting kinases for personalized medicine. RESULTS: In this study, we propose a multi-component Quantitative Structure-Mutation-Activity Relationship Tests (QSMART) model and neural networks framework for providing explainable models of protein kinase inhibition and drug response ([Formula: see text]) profiles in cell lines. Using non-small cell lung cancer as a case study, we show that interaction terms that capture associations between drugs, pathways, and mutant kinases quantitatively contribute to the response of two EGFR inhibitors (afatinib and lapatinib). In particular, protein-protein interactions associated with the JNK apoptotic pathway, associations between lung development and axon extension, and interaction terms connecting drug substructures and the volume/charge of mutant residues at specific structural locations contribute significantly to the observed [Formula: see text] values in cell-based assays. CONCLUSIONS: By integrating multi-omics data in the QSMART model, we not only predict drug responses in cancer cell lines with high accuracy but also identify features and explainable interaction terms contributing to the accuracy. Although we have tested our multi-component explainable framework on protein kinase inhibitors, it can be extended across the proteome to investigate the complex relationships connecting genotypes and drug sensitivity profiles.


Assuntos
Redes Neurais de Computação , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Afatinib/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Lapatinib/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Medicina de Precisão , Mapas de Interação de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia
6.
Anticancer Res ; 40(10): 5757-5764, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988903

RESUMO

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/uso terapêutico , Adulto , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão
7.
J Cancer Res Ther ; 16(4): 930-932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930144

RESUMO

The efficacy of treatments in patients with nonsmall cell lung cancer (NSCLC) with leptomeningeal metastases (LMs) remains unclear. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play an important role in the treatment of patients with NSCLC. However, few studies have investigated the efficacy of combination therapy with TKIs and whole brain radiotherapy (WBRT) in patients with NSCLC/LM. We report here the case of a male patient in his 60s with adenocarcinoma who underwent lobectomy of the right upper lobe. The cancer was classified as pT1bN1M0 Stage IIA, and a mutational analysis revealed the presence of an EGFR mutation. However, 6 months after standard chemotherapy, LM had developed and WBRT was administered. Gefitinib (250 mg/day) was administered after WBRT. The patient remained free of significant recurrent disease for 57 months after WBRT was administered. Combination therapy with TKIs and WBRT is associated with relatively long survival times in patients with LM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/radioterapia , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia , Cisplatino/administração & dosagem , Irradiação Craniana/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Gefitinibe/administração & dosagem , Humanos , Neoplasias Pulmonares/patologia , Masculino , Carcinomatose Meníngea/secundário , Pessoa de Meia-Idade , Mutação , Resultado do Tratamento
8.
PLoS One ; 15(8): e0237790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810185

RESUMO

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from 0.1% to 10.6% over the evaluated period while erlotinib use ranged from 3.4% to 5.4%. Factors associated with no EGFR testing were older age, male gender, enrollment in Medicaid or Medicare, smoking, and geographic region. Factors associated with not receiving erlotinib included older age, male gender, enrollment in Medicare or Medicaid, and living in moderate to high poverty. Survival analysis demonstrated EGFR testing or erlotinib use was associated with a higher likelihood of survival. EGFR testing and erlotinib prescribing were slow to be implemented in our predominantly rural state. While population-level factors likely contributed, patient factors, including geographic location (areas with high poverty rates and rural regions) and insurance type, were associated with lack of use, highlighting rural disparities in the implementation of cancer precision medicine.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Testes Genéticos/estatística & dados numéricos , Neoplasias Pulmonares/tratamento farmacológico , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/estatística & dados numéricos , Prescrições de Medicamentos/economia , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/economia , Uso de Medicamentos/estatística & dados numéricos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Testes Genéticos/economia , Disparidades em Assistência à Saúde/economia , Humanos , Kentucky/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Medicaid/economia , Medicaid/estatística & dados numéricos , Medicare/economia , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Pobreza/estatística & dados numéricos , Medicina de Precisão/economia , Medicina de Precisão/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Estados Unidos , Adulto Jovem
9.
PLoS One ; 15(8): e0237976, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822399

RESUMO

Environmental exposure to arsenite (As3+) has a strong association with the development of human urothelial cancer (UC) and is the 5th most common cancer in men and the 12th most common cancer in women. Muscle invasive urothelial cancer (MIUC) are grouped into basal or luminal molecular subtypes based on their gene expression profile. The basal subtype is more aggressive and can be associated with squamous differentiation, characterized by high expression of keratins (KRT1, 5, 6, 14, and 16) and epidermal growth factor receptor (EGFR) within the tumors. The luminal subtype is less aggressive and is predominately characterized by elevated gene expression of peroxisome proliferator-activated receptor- gamma (PPARγ) and forkhead box protein A1 (FOXA1). We have previously shown that As3+-transformed urothelial cells (As-T) exhibit a basal subtype of UC expressing genes associated with squamous differentiation. We hypothesized that the molecular subtype of the As-T cells could be altered by inducing the expression of PPARγ and/or inhibiting the proliferation of the cells. Non-transformed and As-T cells were treated with Troglitazone (TG, PPARG agonist, 10 µM), PD153035 (PD, an EGFR inhibitor, 1 µM) or a combination of TG and PD for 3 days. The results obtained demonstrate that treatment of the As-T cells with TG upregulated the expression of PPARγ and FOXA1 whereas treatment with PD decreased the expression of some of the basal keratins. However, a combined treatment of TG and PD resulted in a consistent decrease of several proteins associated with the basal subtype of bladder cancers (KRT1, KRT14, KRT16, P63, and TFAP2A). Our data suggests that activation of PPARγ while inhibiting cell proliferation facilitates the regulation of genes involved in maintaining the luminal subtype of UC. In vivo animal studies are needed to address the efficacy of using PPARγ agonists and/or proliferation inhibitors to reduce tumor grade/stage of MIUC.


Assuntos
Arsenitos/farmacologia , Proliferação de Células/efeitos dos fármacos , PPAR gama/metabolismo , Troglitazona/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Queratinas/genética , Queratinas/metabolismo , Camundongos , Camundongos Nus , PPAR gama/agonistas , Quinazolinas/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Transplante Heterólogo , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
10.
Dermatol Online J ; 26(6)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32815691

RESUMO

Cutaneous side effects such as acneiform eruption, xerosis, and paronychia are frequently observed in patients undergoing treatment with epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer and other solid tumors. Interestingly, these side effects appear to positively correlate with length of remission, indicating that disruption of homeostatic EGFR signaling in the skin may serve as a marker of therapeutic EGFR inhibition in tumors. We report the case of a woman with metastatic lung cancer in remission being treated with the EGFR inhibitor, erlotinib, who experienced numerous commonly occurring adverse cutaneous reactions early in her treatment, and after two years of treatment developed eruptive nevi as well as a nevoid melanoma. Changes in pigmented lesions and the development of melanoma have been described during treatment with the BRAF inhibitor, vemurafenib, and are believed to relate to paradoxical activation of BRAF and the MAPK pathway. We speculate that a similar mechanism may occur during treatment with EGFR inhibitors. Therefore, thorough skin examinations are essential for patients undergoing long term treatment with erlotinib.


Assuntos
Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Nevo/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/induzido quimicamente , Idoso , Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/induzido quimicamente
11.
Medicine (Baltimore) ; 99(32): e20683, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769861

RESUMO

BACKGROUND: In China, traditional Chinese medicine (TCM) is an increasingly important part of the treatment of non-small cell lung cancer (NSCLC), which usually includes a combination of prescription and syndrome differentiation. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been proven to be the first-line drugs for the treatment of advanced EGFR mutation-positive NSCLC. In China, EGFR-TKIs are used in combination with traditional Chinese medicines to reduce side effects and/or enhance effectiveness. Nevertheless, the relationship between TCMs and EGFR-TKIs remain unclear. This meta-review aimed to explore the clinical evidence of TCMs combined with EGFR-TKIs in the treatment of NSCLC. METHODS: Related studies were found by searching the databases of EMBASE, PubMed, Web of Science, MEDLINE, Cochrane library database, China Academic Journals (CNKI), Wanfang and Weipu. This study included 57 randomized controlled trials, all of these were processed by Stata software (version 12.0). In the study, all the materials are published articles, patient anonymity and informed consent and ethics Approval/Institutional review board are not necessary. RESULTS: This study demonstrated that the objective response rate was higher in the group of TCMs plus EGFR-TKIs than in the group of EGFR-TKIs alone (risk ratios 1.39, 95% confidence intervals [1.29, 1.50]). Further research of specific herbal medicines showed that Huangqi, Baishu, Fuling, Gancao, Maidong, Baihuashecao, Shashen, Dangshen and Renshen, had significant higher contributions to results. CONCLUSION: TCMs may improve the efficacy of EGFR-TKIs in the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/terapia , Medicina Tradicional Chinesa , Inibidores de Proteínas Quinases/uso terapêutico , Terapia Combinada , Humanos
12.
Nat Commun ; 11(1): 3660, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694521

RESUMO

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Adulto , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Fosforilação/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise/efeitos dos fármacos , Taxa de Sobrevida , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Proc Natl Acad Sci U S A ; 117(32): 19507-19516, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32723814

RESUMO

Previous analysis of postentry events revealed that human cytomegalovirus (HCMV) displays a unique, extended nuclear translocation pattern in monocytes. We determined that c-Src signaling through pentamer engagement of integrins is required upon HCMV entry to avoid sorting of the virus into late endosomes and subsequent degradation. To follow up on this previous study, we designed experiments to investigate how HCMV-induced signaling through the other major axis-the epidermal growth factor receptor (EGFR) kinase-regulates viral postentry events. Here we show that HCMV induces chronic and functional EGFR signaling that is distinct to the virus as compared to the natural EGFR ligand: EGF. This chronic EGFR kinase activity in infected monocytes is required for the proper subcellular localization of the viral particle during trafficking events, as well as for promoting translocation of viral DNA into the host nucleus. Our data indicate that HCMV glycoprotein B (gB) binds to EGFR at the monocyte surface, the virus and EGFR are internalized together, and gB remains bound to EGFR throughout viral postentry events until de-envelopment to promote the chronic EGFR kinase activity required for viral trafficking and nuclear translocation. These data highlight how initial EGFR signaling via viral binding is necessary for entry, but not sufficient to promote each viral trafficking event. HCMV appears to manipulate the EGFR kinase postentry, via gB-EGFR interaction, to be active at the critical points throughout the trafficking process that leads to nuclear translocation and productive infection of peripheral blood monocytes.


Assuntos
Núcleo Celular/metabolismo , Citomegalovirus/fisiologia , Monócitos/virologia , Proteínas do Envelope Viral/metabolismo , Núcleo Celular/virologia , Células Cultivadas , DNA Viral/metabolismo , Endossomos/metabolismo , Endossomos/virologia , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Monócitos/metabolismo , Ligação Proteica , Transdução de Sinais , Rede trans-Golgi/metabolismo , Rede trans-Golgi/virologia
14.
J Oncol Pharm Pract ; 26(6): 1452-1460, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32525442

RESUMO

Lung cancer is a complex, genetically heterogeneous disease. It is the most common cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the majority of the diagnosed lung cancer cases. Osimertinib is a new treatment option that demonstrated a superior efficacy over standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or platinum-based chemotherapy. The safety and efficacy of osimertinib (a third generation EGFR-TKIs) were confirmed by well-designed clinical trials. Consequently, osimertinib was considered a first-line treatment option, particularly in patients with EGFR mutant NSCLC. It has been approved by FDA for the treatment of advance or metastatic NSCLC patients with specific EGFR-mutant NSCLC. As an active member of the multidisciplinary team, pharmacist has a promising role in assuring safe, effective and cost-effective treatment in patient with NSCLC. This review article aims to highlight the latest evidence about osimertinib use as a new treatment option in the clinical practice and to review the potential pharmacist key roles in NSCLC patient care.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Humanos , Mutação , Farmacêuticos/organização & administração , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
15.
J Med Chem ; 63(11): 5752-5762, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32484346

RESUMO

Resistance to chemotherapy in advanced cancers can be mediated by different factors such as epidermal growth factor receptor (EGFR) overexpression and DNA repair enzymes. Therefore, current standards of care usually involve combinations of multiple treatments. Here, to reduce the adverse effects of multiple drug combinations and improve outcome, we proposed a single drug approach to block multiple overlapping effects that characterize chemoresistance. Thus, we designed a new linker that allows assembly of multiple functions (e.g., inhibition of EGFR phosphorylation, induction of DNA lesions, and blockade of their repair) into a single molecule. This led to the successful synthesis of a novel and potent combi-molecule JS230. Here, we demonstrated that in resistant prostate cancer cells overexpressing EGFR, it was capable of (a) inhibiting EGFR in a dose-dependent manner, (b) damaging DNA, and (c) sustaining the damage by inhibiting the DNA repair protein poly(ADP-ribose) polymerase (PARP). The triple mechanism of action of JS230 cumulated into growth inhibitory potency superior to that of classical two- or three-drug combinations.


Assuntos
Dano ao DNA , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Poli(ADP-Ribose) Polimerases/química , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Masculino , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos
16.
Cancer Treat Rev ; 86: 102023, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32474402

RESUMO

Colorectal cancer (CRC) represents a global health problem, being one of the most diagnosed and aggressive tumors. Cetuximab and panitumumab monoclonal antibodies (mAbs) in combination with chemotherapy are an effective strategy for patients with RAS Wild Type (WT) metastatic colorectal cancer (mCRC). However, tumors are often unresponsive or develop resistance. In the last years, molecular alterations in principal oncogenes (RAS, BRAF, PI3KCA, PTEN) in the downstream pathway of the epidermal growth factor receptor (EGFR) and in other receptors (HER2, MET) that converge on MAPK-ERK signalling have been identified as novel mechanisms of resistance to anti-EGFR strategies. However, further efforts are needed to better stratify CRCs and ensure more individualized treatments. Herein, we describe the consolidated molecular drivers of resistance and the therapeutic strategies available so far, with an overview on potential biomarkers of response that could be integrated in clinical practice.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Receptores ErbB/antagonistas & inibidores , Humanos , Metástase Neoplásica , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Breast Cancer Res ; 22(1): 66, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552913

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by high rates of recurrence and poor overall survival. This is due, in part, to a deficiency of targeted therapies, making it essential to identify therapeutically targetable driver pathways of this disease. While epidermal growth factor receptor (EGFR) is expressed in 60% of TNBCs and drives disease progression, attempts to inhibit EGFR in unselected TNBC patients have had a marginal impact on outcomes. Hence, we sought to identify the mechanisms that dictate EGFR expression and inhibitor response to provide a path for improving the utility of these drugs. In this regard, the majority of TNBCs express low levels of the transcription factor, Krüppel-like factor 4 (KLF4), while a small subset is associated with high expression. KLF4 and EGFR have also been reported to have opposing actions in TNBC. Thus, we tested whether KLF4 controls the expression of EGFR and cellular response to its pharmacological inhibition. METHODS: KLF4 was transiently overexpressed in MDA-MB-231 and MDA-MB-468 cells or silenced in MCF10A cells. Migration and invasion were assessed using modified Boyden chamber assays, and proliferation was measured by EdU incorporation. Candidate downstream targets of KLF4, including EGFR, were identified using reverse phase protein arrays of MDA-MB-231 cells following enforced KLF4 expression. The ability of KLF4 to suppress EGFR gene and protein expression and downstream signaling was assessed by RT-PCR and western blot, respectively. ChIP-PCR confirmed KLF4 binding to the EGFR promoter. Response to erlotinib in the context of KLF4 overexpression or silencing was assessed using cell number and dose-response curves. RESULTS: We report that KLF4 is a major determinant of EGFR expression and activity in TNBC cells. KLF4 represses transcription of the EGFR gene, leading to reduced levels of total EGFR, its activated/phosphorylated form (pEGFR), and its downstream signaling intermediates. Moreover, KLF4 suppression of EGFR is a necessary intermediary step for KLF4 to inhibit aggressive TNBC phenotypes. Most importantly, KLF4 dictates the sensitivity of TNBC cells to erlotinib, an FDA-approved inhibitor of EGFR. CONCLUSIONS: KLF4 is a major regulator of the efficacy of EGFR inhibitors in TNBC cells that may underlie the variable effectiveness of such drugs in patients.


Assuntos
Antineoplásicos/farmacologia , Cloridrato de Erlotinib/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fosforilação , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
18.
Bull Cancer ; 107(7-8): 792-799, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32591138

RESUMO

Anal canal cancer is a rare disease that accounts for 2.5% of digestive cancers. Squamous cell carcinomas are the most common histological form. Their incidence is in progression, probably due to the increase in Human Papilloma Virus infections. Metastatic forms account for 20% of anal canal cancers considering synchronous forms or metastatic recurrence of an initially localised disease. Their prognosis remains poor with an estimated 5-year survival rate of 30%. The first-line therapeutic standard based on the combination of cisplatin with 5-Fluorouracil has recently been challenged by carboplatin - paclitaxel and docetaxel, cisplatin and 5-Fluorouracil regimens which are becoming new treatment options. In second-line setting, there is no international consensus. Anti-EGFRs and immunotherapy in combination or not with other molecules are promising but these results need to be confirmed. In this review, we report current and future data in the management of squamous cell carcinomas of the anal canal in unresectable locoregional recurrence or at metastatic stage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Ânus/mortalidade , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Fluoruracila/administração & dosagem , Humanos , Imunoterapia/métodos , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida
19.
Adv Cancer Res ; 147: 109-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593399

RESUMO

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) are among the first layer of molecules that receive, interpret, and transduce signals leading to distinct cancer cell phenotypes. Since the discovery of the tooth-lid factor-later characterized as the epidermal growth factor (EGF)-and its high-affinity binding EGF receptor, HER kinases have emerged as one of the commonly upregulated or hyperactivated or mutated kinases in epithelial tumors, thus allowing HER1-3 family members to regulate several hallmarks of cancer development and progression. Each member of the HER family exhibits shared and unique structural features to engage multiple receptor activation modes, leading to a range of overlapping and distinct phenotypes. EGFR, the founding HER family member, provided the roadmap for the development of the cell surface RTK-directed targeted cancer therapy by serving as a prototype/precursor for the currently used HER-directed cancer drugs. We herein provide a brief account of the discoveries, defining moments, and historical context of the HER family and guidepost advances in basic, translational, and clinical research that solidified a prominent position of the HER family in cancer research and treatment. We also discuss the significance of HER3 pseudokinase in cancer biology; its unique structural features that drive transregulation among HER1-3, leading to a superior proximal signaling response; and potential role of HER3 as a shared effector of acquired therapeutic resistance against diverse oncology drugs. Finally, we also narrate some of the current drawbacks of HER-directed therapies and provide insights into postulated advances in HER biology with extensive implications of these therapies in cancer research and treatment.


Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais
20.
Adv Cancer Res ; 147: 161-188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593400

RESUMO

The Epidermal Growth Factor Receptor (EGFR) is frequently expressed at elevated levels in different forms of cancer and expression often correlates positively with cancer progression and poor prognosis. Different mutant forms of this protein also contribute to cancer heterogeneity. A constitutively active form of EGFR, EGFRvIII is one of the most important variants. EGFR is responsible for the maintenance and functions of cancer stem cells (CSCs), including stemness, metabolism, immunomodulatory-activity, dormancy and therapy-resistance. EGFR regulates these pathways through several signaling cascades, and often cooperates with other RTKs to exert further control. Inhibitors of EGFR have been extensively studied and display some anticancer efficacy. However, CSCs can also acquire resistance to EGFR inhibitors making effective therapy even more difficult. To ameliorate this limitation of EGFR inhibitors when used as single agents, it may be of value to simultaneously combine multiple EGFR inhibitors or use EGFR inhibitors with regulators of other important cancer phenotype regulating molecules, such as STAT3, or involved in important processes such as DNA repair. These combinatorial approaches require further experimental confirmation, but if successful would expand and improve therapeutic outcomes employing EGFR inhibitors as one arm of the therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias/enzimologia , Neoplasias/patologia , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Progressão da Doença , Receptores ErbB/genética , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Fosforilação , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...