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

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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Zhang L,Yao Y,Zhang S,Liu Y,Guo H,Ahmed M,Bell T,Zhang H,Han G,Lorence E,Badillo M,Zhou S,Sun Y,Di Francesco ME,Feng N,Haun R,Lan R,Mackintosh SG,Mao X,Song X,Zhang J,Pham LV,Lorenzi PL,Marszalek J,Heffern

doi

10.1126/scitranslmed.aau1167

subject

Has Abstract

pub_date

2019-05-08 00:00:00

issue

491

eissn

1946-6234

issn

1946-6242

pii

11/491/eaau1167

journal_volume

11

pub_type

杂志文章

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