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Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance. (Redox Biol, Dec 2018)

Hirpara J1, Eu JQ1, Tan JKM2, Wong AL3, Clement MV4, Kong LR1, Ohi N5, Tsunoda T6, Qu J7, Goh BC8, Pervaiz S9.

Author information
1Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
2Genome 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.
3Cancer 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.
4Department 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.
5Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Shiga 520-0106, Japan.
6Otsuka Pharmaceutical Co. Ltd., Tokyo 101-8535, Japan.
7Department of Physiology and Medical Science Cluster Cancer ProgramYong Loo Lin School of Medicine, National University of Singapore, Singapore 119753, Singapore.
8Cancer 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.
9Department 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.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords: Metabolic reprogramming; OXPHOS; Oncogene-addiction; STAT3

PMID: 30642723