| Literature DB >> 31068440 |
Liang Zhang1, Yixin Yao1, Shaojun Zhang2, Yang Liu1, Hui Guo1, Makhdum Ahmed1, Taylor Bell1, Hui Zhang1, Guangchun Han2, Elizabeth Lorence1, Maria Badillo1, Shouhao Zhou3, Yuting Sun4, M Emilia Di Francesco4, Ningping Feng4, Randy Haun5, Renny Lan6, Samuel G Mackintosh6, Xizeng Mao2, Xingzhi Song2, Jianhua Zhang2, Lan V Pham7, Philip L Lorenzi8, Joseph Marszalek4, Tim Heffernan4, Giulio Draetta2,4, Philip Jones4, Andrew Futreal2, Krystle Nomie1, Linghua Wang9, Michael Wang10,11.
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.Entities:
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Year: 2019 PMID： 31068440 DOI： 10.1126/scitranslmed.aau1167
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956