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

• Published in: Cancer discovery Vol. 7; no. 12; pp. 1450 - 1463
• Main Authors: Malone, Clare F., Emerson, Chloe, Ingraham, Rachel, Barbosa, William, Guerra, Stephanie, Yoon, Haejin, Liu, Lin L., Michor, Franziska, Haigis, Marcia, Macleod, Kay F., Maertens, Ophélia, Cichowski, Karen
• Format: Journal Article
• Language: English
• Published: United States 01.12.2017
• Subjects: Carrier Proteins - genetics; Carrier Proteins - metabolism; Histone Deacetylase Inhibitors - therapeutic use; Humans; Oxidative Stress; Signal Transduction; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-17-0177

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