mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors.
Cancer Discov
; 7(12): 1450-1463, 2017 12.
Article
en En
| MEDLINE
| ID: mdl-28963352
ABSTRACT
Although agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here, we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin antioxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating apoptosis signal-regulating kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together, these studies identify a promising therapeutic combination for several currently untreatable malignancies and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.Significance:
There are no effective therapies for NF1- or RAS-mutant cancers. We show that combined mTOR/HDAC inhibitors kill these RAS-driven tumors by causing catastrophic oxidative stress. This study identifies a promising therapeutic combination and demonstrates that selective enhancement of oxidative stress may be more broadly exploited for developing cancer therapies. Cancer Discov; 7(12); 1450-63. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Portadoras
/
Inhibidores de Histona Desacetilasas
/
Serina-Treonina Quinasas TOR
Límite:
Humans
Idioma:
En
Revista:
Cancer Discov
Año:
2017
Tipo del documento:
Article