Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.
Nat Med
; 22(3): 262-9, 2016 Mar.
Article
en En
| MEDLINE
| ID: mdl-26828195
ABSTRACT
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Quinazolinas
/
ARN Mensajero
/
Regulación Neoplásica de la Expresión Génica
/
Carcinoma de Pulmón de Células no Pequeñas
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Resistencia a Antineoplásicos
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Inhibidores de Proteínas Quinasas
/
Receptores ErbB
/
Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos