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Cancer Discov. 2017 Dec;7(12):1450-1463. doi: 10.1158/2159-8290.CD-17-0177. Epub 2017 Sep 29.

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors.

Author information

1
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2
Harvard Medical School, Boston, Massachusetts.
3
Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
The Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois.
6
Ludwig Center at Harvard, Boston, Massachusetts.
7
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. kcichowski@rics.bwh.harvard.edu.

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.

PMID:
28963352
PMCID:
PMC5718976
[Available on 2018-12-01]
DOI:
10.1158/2159-8290.CD-17-0177
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