MED12 controls the response to multiple cancer drugs through regulation of TGF-ß receptor signaling.
Cell
; 151(5): 937-50, 2012 Nov 21.
Article
en En
| MEDLINE
| ID: mdl-23178117
ABSTRACT
Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-ßR2 through physical interaction. MED12 suppression therefore results in activation of TGF-ßR signaling, which is both necessary and sufficient for drug resistance. TGF-ß signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-ßR signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Receptores de Factores de Crecimiento Transformadores beta
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Resistencia a Antineoplásicos
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Complejo Mediador
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Neoplasias
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Cell
Año:
2012
Tipo del documento:
Article
País de afiliación:
Países Bajos