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DC Field | Value | Language |
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dc.citation.endPage | 1463 | - |
dc.citation.number | 12 | - |
dc.citation.startPage | 1450 | - |
dc.citation.title | CANCER DISCOVERY | - |
dc.citation.volume | 7 | - |
dc.contributor.author | Malone, Clare F. | - |
dc.contributor.author | Emerson, Chloe | - |
dc.contributor.author | Ingraham, Rachel | - |
dc.contributor.author | Barbosa, William | - |
dc.contributor.author | Guerra, Stephanie | - |
dc.contributor.author | Yoon, Haejin | - |
dc.contributor.author | Liu, Lin L. | - |
dc.contributor.author | Michor, Franziska | - |
dc.contributor.author | Haigis, Marcia | - |
dc.contributor.author | Macleod, Kay F. | - |
dc.contributor.author | Maertens, Ophelia | - |
dc.contributor.author | Cichowski, Karen | - |
dc.date.accessioned | 2023-12-21T21:17:57Z | - |
dc.date.available | 2023-12-21T21:17:57Z | - |
dc.date.created | 2022-03-08 | - |
dc.date.issued | 2017-12 | - |
dc.description.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. (C) 2017 AACR. | - |
dc.identifier.bibliographicCitation | CANCER DISCOVERY, v.7, no.12, pp.1450 - 1463 | - |
dc.identifier.doi | 10.1158/2159-8290.CD-17-0177 | - |
dc.identifier.issn | 2159-8274 | - |
dc.identifier.scopusid | 2-s2.0-85035045084 | - |
dc.identifier.uri | https://scholarworks.unist.ac.kr/handle/201301/58163 | - |
dc.identifier.wosid | 000417070700026 | - |
dc.language | 영어 | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.title | mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors | - |
dc.type | Article | - |
dc.description.isOpenAccess | FALSE | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.relation.journalResearchArea | Oncology | - |
dc.type.docType | Article | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | THIOREDOXIN | - |
dc.subject.keywordPlus | CANCER | - |
dc.subject.keywordPlus | APOPTOSIS | - |
dc.subject.keywordPlus | TRANSCRIPTION | - |
dc.subject.keywordPlus | SENSITIVITY | - |
dc.subject.keywordPlus | GLUTATHIONE | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | ONCOGENE | - |
dc.subject.keywordPlus | THERAPY | - |
dc.subject.keywordPlus | PROTEIN | - |
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