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Sci Transl Med. 2019 May 8;11(491). pii: eaau1167. doi: 10.1126/scitranslmed.aau1167.

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

Author information

1
Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
6
Department of Biochemistry and Molecular Biology and Proteomics Core Facility, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
7
Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Proteomics and Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. lwang22@mdanderson.org miwang@mdanderson.org.
10
Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. lwang22@mdanderson.org miwang@mdanderson.org.
11
Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

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.

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