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1.
Nature ; 620(7973): 393-401, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37407818

RESUMO

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.


Assuntos
Citidina Desaminase , Neoplasias Pulmonares , Humanos , Citidina Desaminase/deficiência , Citidina Desaminase/efeitos dos fármacos , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Quebras de DNA de Cadeia Dupla , Instabilidade Genômica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Mutação , Resistencia a Medicamentos Antineoplásicos
2.
BMC Med Educ ; 22(1): 600, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927659

RESUMO

BACKGROUND: Rounds are a foundational practice in patient care and education in the inpatient healthcare environment, but increased demands on inpatient teams have led to dissatisfaction with inefficient, ineffective rounds. In this study, we describe the design, implementation, and evaluation of a novel rounding framework ("NET Rounding") that provides behaviorally-based strategies to inpatient teams to achieve efficient rounds while preserving patient safety and education. METHODS: NET Rounding consists of nine recommendations divided into three categories: Novel rounding strategies, shared Expectations, and Time management. This framework was introduced as a bundled intervention at a single-site, quaternary-care, academic hospital from March-May 2021. Eighty-three residents and 64 attendings rotated on the inpatient teaching service during the intervention period. Participants were surveyed before, during, and after their rotation about rounding's contribution to educational value, patient safety, resident duty hour violations and rotation experience. Additionally, rounding duration was recorded daily by team attendings. RESULTS: Thirty-two residents (38.5%) and 45 attendings (70%) completed post-intervention surveys. Rounding duration was recorded on 529/626 rounding days (80.6%) and resulted in achieving efficient rounds on 412/529 days (77.9%). Residents reported improvement in perceived patient safety (54 to 84%, p = 0.0131) and educational value of rounds (38 to 69%, p = 0.0213) due to NET Rounding; no change was observed amongst attendings in these areas (79 to 84% and 70 to 80%, p = 0.7083 and 0.4237, respectively). Overall, 29/32 residents (91%) and 33/45 attendings (73%) reported a positive impact on rotation experience. CONCLUSIONS: NET Rounding enabled inpatient teaching teams to complete rounds more efficiently while preserving patient safety and education.


Assuntos
Internato e Residência , Visitas de Preceptoria , Humanos , Assistência ao Paciente , Inquéritos e Questionários
3.
Blood Cells Mol Dis ; 60: 44-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27519944

RESUMO

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL. Increased expression of LOX-1 has been demonstrated in atherosclerotic lesions and diabetic vasculopathy. In this study, we investigate the expression of LOX-1 receptor in sickle cell disease (SCD) vasculopathy. Expression of LOX-1 in brain vascular endothelium is markedly increased and LOX-1 gene expression is upregulated in cultured human brain microvascular endothelial cells by incubation with SCD erythrocytes. Also, the level of circulating soluble LOX-1 concentration is elevated in the plasma of SCD patients. Increased LOX-1 expression in endothelial cells is potentially involved in the pathogenesis of SCD vasculopathy. Soluble LOX-1 concentration in SCD may provide a novel biomarker for risk stratification of sickle cell vascular complications.


Assuntos
Anemia Falciforme/complicações , Receptores Depuradores Classe E/fisiologia , Doenças Vasculares/etiologia , Adolescente , Adulto , Coleta de Amostras Sanguíneas , Encéfalo/patologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Células Endoteliais/química , Feminino , Regulação da Expressão Gênica , Humanos , Lipoproteínas LDL , Masculino , Pessoa de Meia-Idade , Receptores Depuradores Classe E/sangue , Receptores Depuradores Classe E/genética
4.
Clin Cancer Res ; 24(1): 197-208, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29051323

RESUMO

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR.


Assuntos
Proteína 11 Semelhante a Bcl-2/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Compostos de Anilina/farmacologia , Animais , Apoptose/genética , Ciclo Celular/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Camundongos , Mutação , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Sulfonamidas/farmacologia
5.
Cancer Discov ; 8(12): 1598-1613, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30254092

RESUMO

BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in KRAS-mutant non-small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone. Susceptibility to BH3 mimetics that target either MCL1 or BCL-xL was determined by the differential binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to MCL1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL2 family proteins for KRAS-mutant NSCLC. SIGNIFICANCE: Defining the molecular basis for MCL1 versus BCL-xL dependency will be essential for effective prioritization of BH3 mimetic combination therapies in the clinic. We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of KRAS-mutant NSCLCs treated with MEK inhibitors.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Células A549 , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Knockout , Camundongos Nus , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Nat Med ; 22(3): 262-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26828195

RESUMO

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , RNA Mensageiro/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Gefitinibe , Humanos , Técnicas In Vitro , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Mutação , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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