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|Title:||Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance||Authors:||Hirpara, Jayshree
Eu, Jie Qing
Tan, Joanna Kia Min
Wong, Andrea L.
Kong, Li Ren
Goh, Boon Cher
|Keywords:||Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
|Issue Date:||1-Jul-2019||Publisher:||ELSEVIER||Citation:||Hirpara, Jayshree, Eu, Jie Qing, Tan, Joanna Kia Min, Wong, Andrea L., Clement, Marie-Veronique, Kong, Li Ren, Ohi, Naoto, Tsunoda, Takeshi, Qu, Jianhua, Goh, Boon Cher, Pervaiz, Shazib (2019-07-01). Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance. REDOX BIOLOGY 25. ScholarBank@NUS Repository. https://doi.org/10.1016/j.redox.2018.101076||Abstract:||© 2018 The Authors 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.||Source Title:||REDOX BIOLOGY||URI:||https://scholarbank.nus.edu.sg/handle/10635/175481||ISSN:||22132317||DOI:||10.1016/j.redox.2018.101076|
|Appears in Collections:||Staff Publications|
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