Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma

Liang Zhang, Yixin Yao, Shaojun Zhang, Yang Liu, Hui Guo, Makhdum Ahmed, Taylor Bell, Hui Zhang, Guangchun Han, Elizabeth Lorence, Maria Badillo, Shouhao Zhou, Yuting Sun, M. Emilia Di Francesco, Ningping Feng, Randy Haun, Renny Lan, Samuel G. MacKintosh, Xizeng Mao, Xingzhi SongJianhua Zhang, Lan V. Pham, Philip L. Lorenzi, Joseph Marszalek, Tim Heffernan, Giulio Draetta, Philip Jones, Andrew Futreal, Krystle Nomie, Linghua Wang, Michael Wang

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

Original languageEnglish (US)
Article numbereaau1167
JournalScience Translational Medicine
Volume11
Issue number491
DOIs
StatePublished - 2019

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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