Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance
Jayshree Hirpara,
Jie Qing Eu,
Joanna Kia Min Tan,
Andrea L. Wong,
Marie-Veronique Clement,
Li Ren Kong,
Naoto Ohi,
Takeshi Tsunoda,
Jianhua Qu,
Boon Cher Goh,
Shazib Pervaiz
Affiliations
Jayshree Hirpara
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore
Jie Qing Eu
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore
Joanna Kia Min Tan
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
Andrea L. Wong
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
Marie-Veronique Clement
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
Li Ren Kong
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore
Naoto Ohi
Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Shiga 520-0106, Japan
Takeshi Tsunoda
Otsuka Pharmaceutical Co. Ltd., Tokyo 101-8535, Japan
Jianhua Qu
Department of Physiology and Medical Science Cluster Cancer ProgramYong Loo Lin School of Medicine, National University of Singapore, Singapore 119753, Singapore
Boon Cher Goh
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; Corresponding authors at: National University Cancer Institute, National University Health System, Singapore 119074, Singapore.
Shazib Pervaiz
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; Corresponding authors at: National University Cancer Institute, National University Health System, Singapore 119074, Singapore.
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
