Journal
REDOX BIOLOGY
Volume 25, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2018.101076
Keywords
Metabolic reprogramming; OXPHOS; Oncogene-addiction; STAT3
Categories
Funding
- National Medical Research Council of Singapore [NMRC/CSA/021/2010]
- NMRC Bench to Bedside (BOB)
- National University Health System Clinician Scientist Program Clinical Science Unit (CSU)
- National Medical Research Council-Clinician Scientist Individual Research Grant [NMRC/CIRG/1433/2015]
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The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting.
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