Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Banco de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Cancer Discov ; 13(1): 41-55, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36355783

RESUMEN

With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance. SIGNIFICANCE: Clinical resistance to KRASG12C-EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches. This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Neoplasias Colorrectales , Resistencia a Antineoplásicos , Animales , Humanos , Resistencia a Antineoplásicos/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , Receptores ErbB , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Mutación
2.
Nat Med ; 25(4): 575-582, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30833749

RESUMEN

Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.


Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Leptina/farmacología , Obesidad/tratamiento farmacológico , Receptores Tipo I de Interleucina-1/metabolismo , Triterpenos/uso terapéutico , Animales , Fármacos Antiobesidad/farmacología , Dieta , Células HEK293 , Humanos , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Triterpenos Pentacíclicos , Triterpenos/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA