Research ArticleCancer

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

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaau1167
DOI: 10.1126/scitranslmed.aau1167

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Dismantling lymphoma metabolism

Mantle cell lymphoma is a B cell malignancy that often responds to initial treatment with ibrutinib, an inhibitor of Bruton’s tyrosine kinase. Unfortunately, the therapeutic response is typically short lived for reasons that are not yet fully understood. Zhang et al. found that resistance to ibrutinib in mantle cell lymphoma can be associated with metabolic reprogramming and a shift toward reliance on glutaminolysis and oxidative phosphorylation by the cancer cells. The authors demonstrated that these drug-resistant cells can be effectively targeted with a small-molecule inhibitor of oxidative phosphorylation, showing promising therapeutic results in patient-derived mouse models.

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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