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1.
Semin Cancer Biol ; 61: 167-179, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31562956

RESUMEN

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.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Mutación , Alelos , Sustitución de Aminoácidos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exones , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología
2.
Biochem Biophys Res Commun ; 501(1): 124-130, 2018 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-29709482

RESUMEN

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.


Asunto(s)
Colágeno/metabolismo , Receptor con Dominio Discoidina 2/metabolismo , Sustitución de Aminoácidos , Membrana Celular/metabolismo , Receptor con Dominio Discoidina 2/química , Receptor con Dominio Discoidina 2/genética , Células HEK293 , Humanos , Integrinas/metabolismo , Microscopía Fluorescente , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Fosforilación , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismo , Tirosina/metabolismo
4.
Dis Model Mech ; 13(7)2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32493768

RESUMEN

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.


Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Proteínas de Neoplasias/metabolismo , Proteoma , Proteómica , Células del Estroma/metabolismo , Espectrometría de Masas en Tándem , Animales , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Comunicación Celular , Línea Celular Tumoral , Cromatografía Liquida , Bases de Datos de Proteínas , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones SCID , Células 3T3 NIH , Trasplante de Neoplasias , Especificidad de la Especie , Células del Estroma/patología , Microambiente Tumoral
5.
Essays Biochem ; 62(4): 583-593, 2018 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-30072489

RESUMEN

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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de Señal , Biología de Sistemas , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Recuperativa
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