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Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors
- Source :
- Redox Biology, Vol 25, Iss, Pp-(2019), Redox Biology
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism.<br />Highlights • Metabolic reprogramming of cancer cells is one of the hallmarks of cancer. • STAT3 and OXPHOS upregulation are resistance mechanisms in oncogene-addicted tumors. • mSTAT3 has a role in the direct, non-transcriptional regulation of OXPHOS. • Combining OXPHOS inhibitors with TKIs reverses resistance to targeted therapy.
- Subjects :
- STAT3 Transcription Factor
0301 basic medicine
Cell signaling
medicine.medical_treatment
Clinical Biochemistry
Phenformin
OXPHOS inhibitors
Biochemistry
Article
Oxidative Phosphorylation
STAT3 signaling pathways
Targeted therapy
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Downregulation and upregulation
Cancer cell metabolism
Neoplasms
Animals
Humans
Medicine
lcsh:QH301-705.5
lcsh:R5-920
Oncogene
business.industry
Organic Chemistry
Oncogenes
STAT inhibitors
Mitochondria
Oxidative phosphorylation (OXPHOS)
030104 developmental biology
lcsh:Biology (General)
chemistry
Drug Resistance, Neoplasm
Cancer cell
Cancer research
STAT protein
Signal transduction
lcsh:Medicine (General)
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 22132317
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....2522b0ef291062114b81d0c91a61b0d4