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1.
Dis Model Mech ; 13(7)2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32493768

RESUMO

SWATH-mass spectrometry (MS) enables accurate and reproducible proteomic profiling in multiple model organisms including the mouse. Here, we present a comprehensive mouse reference spectral library (MouseRefSWATH) that permits quantification of up to 10,597 proteins (62.2% of the mouse proteome) by SWATH-MS. We exploit MouseRefSWATH to develop an analytical pipeline for species-specific deconvolution of proteomic alterations in human tumour xenografts (XenoSWATH). This method overcomes the challenge of high sequence similarity between mouse and human proteins, facilitating the study of host microenvironment-tumour interactions from 'bulk tumour' measurements. We apply the XenoSWATH pipeline to characterize an intraductal xenograft model of breast ductal carcinoma in situ and uncover complex regulation consistent with stromal reprogramming, where the modulation of cell migration pathways is not restricted to tumour cells but also operates in the mouse stroma upon progression to invasive disease. MouseRefSWATH and XenoSWATH open new opportunities for in-depth and reproducible proteomic assessment to address wide-ranging biological questions involving this important model organism.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Proteínas de Neoplasias/metabolismo , Proteoma , Proteômica , Células Estromais/metabolismo , Espectrometria de Massas em Tandem , Animais , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Comunicação Celular , Linhagem Celular Tumoral , Cromatografia Líquida , Bases de Dados de Proteínas , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos SCID , Células NIH 3T3 , Transplante de Neoplasias , Especificidade da Espécie , Células Estromais/patologia , Microambiente Tumoral
2.
Semin Cancer Biol ; 61: 167-179, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31562956

RESUMO

Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18-25 of the EGFR gene in NSCLC and are associated with poorer responses to EGFRi. Despite an increased uptake of more sensitive detection methods to identify rare EGFR mutations in patients, our understanding of the biology of these rare EGFR mutations is poor compared to classical mutations. In particular, clinical data focused on these mutations is lacking due to their rarity and challenges in trial recruitment, resulting in an absence of effective treatment strategies for many low frequency EGFR mutations. In this review, we describe the structural and mechanistic features of rare EGFR mutations in NSCLC and discuss the preclinical and clinical evidence for EGFRi response for individual rare EGFR mutations. We also discuss EGFRi sensitivity for complex EGFR mutations, and conclude by offering a perspective on the outstanding questions and future steps required to make advances in the treatment of NSCLC patients that harbour rare EGFR mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Alelos , Substituição de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Éxons , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia
3.
Essays Biochem ; 62(4): 583-593, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30072489

RESUMO

Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais , Biologia de Sistemas , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação
5.
Biochem Biophys Res Commun ; 501(1): 124-130, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29709482

RESUMO

Discoidin Domain Receptor 2 (DDR2) is a collagen-binding receptor tyrosine kinase that initiates delayed and sustained tyrosine phosphorylation signalling. To understand the molecular basis of this unique phosphorylation profile, here we utilise fluorescence microscopy to map the spatiotemporal localisation of DDR2 and tyrosine phosphorylated proteins upon stimulation with collagen. We show that cellular phosphorylated proteins are localised to the interface where DDR2 is in contact with collagen and not in the early endosomes or lysosomes. We find that DDR2 localisation is independent of integrin activation and the key DDR2 signalling effector SHC1. Structure-function analysis reveals that DDR2 mutants defective for collagen binding or kinase activity are unable to localise to the cell surface, demonstrating for the first time that both collagen binding and kinase functions are required for spatial localisation of DDR2. This study provides new insights into the underlying structural features that control DDR2 activation in space and time.


Assuntos
Colágeno/metabolismo , Receptor com Domínio Discoidina 2/metabolismo , Substituição de Aminoácidos , Membrana Celular/metabolismo , Receptor com Domínio Discoidina 2/química , Receptor com Domínio Discoidina 2/genética , Células HEK293 , Humanos , Integrinas/metabolismo , Microscopia de Fluorescência , Mutagênese Sítio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Fosforilação , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Tirosina/metabolismo
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