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

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 <i>NF1</i>-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors <i>in vivo</i> 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 <i>NF1</i>-mutant and <i>KRAS</i>-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.<b>Significance:</b> There are no effective therapies for <i>NF1</i>- or <i>RAS</i>-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. <i>Cancer Discov; 7(12); 1450-63. ©2017 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 1355</i>.