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Redox Biol. 2019 Jul;25:101076. doi: 10.1016/j.redox.2018.101076. Epub 2018 Dec 17.

Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance.

Author information

1
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
2
Genome Institute of Singapore, Singapore 138672, Singapore; Department of Physiology and Medical Science Cluster Cancer ProgramYong Loo Lin School of Medicine, National University of Singapore, Singapore 119753, Singapore.
3
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore; Department of Hematology-Oncology, National University Health System, Singapore 119228, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
4
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore; NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore.
5
Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Shiga 520-0106, Japan.
6
Otsuka Pharmaceutical Co. Ltd., Tokyo 101-8535, Japan.
7
Department of Physiology and Medical Science Cluster Cancer ProgramYong Loo Lin School of Medicine, National University of Singapore, Singapore 119753, Singapore.
8
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore; Department of Hematology-Oncology, National University Health System, Singapore 119228, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; National University Cancer Institute, National University Health System, Singapore 119074, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore. Electronic address: boon_cher_goh@nuhs.edu.sg.
9
Department of Physiology and Medical Science Cluster Cancer ProgramYong Loo Lin School of Medicine, National University of Singapore, Singapore 119753, Singapore; NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore; National University Cancer Institute, National University Health System, Singapore 119074, Singapore; Curtin Health Innovation Research Institute and School of Pharmacy and Biomedical Sciences, Curtin University, Perth 6102, Australia. Electronic address: Shazib_Pervaiz@nuhs.edu.sg.

Abstract

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.

KEYWORDS:

Metabolic reprogramming; OXPHOS; Oncogene-addiction; STAT3

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