TY - JOUR
T1 - Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma
AU - Zhang, Liang
AU - Yao, Yixin
AU - Zhang, Shaojun
AU - Liu, Yang
AU - Guo, Hui
AU - Ahmed, Makhdum
AU - Bell, Taylor
AU - Zhang, Hui
AU - Han, Guangchun
AU - Lorence, Elizabeth
AU - Badillo, Maria
AU - Zhou, Shouhao
AU - Sun, Yuting
AU - Di Francesco, M. Emilia
AU - Feng, Ningping
AU - Haun, Randy
AU - Lan, Renny
AU - MacKintosh, Samuel G.
AU - Mao, Xizeng
AU - Song, Xingzhi
AU - Zhang, Jianhua
AU - Pham, Lan V.
AU - Lorenzi, Philip L.
AU - Marszalek, Joseph
AU - Heffernan, Tim
AU - Draetta, Giulio
AU - Jones, Philip
AU - Futreal, Andrew
AU - Nomie, Krystle
AU - Wang, Linghua
AU - Wang, Michael
N1 - Publisher Copyright:
© 2019 The Authors.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.aau1167
DO - 10.1126/scitranslmed.aau1167
M3 - Article
C2 - 31068440
AN - SCOPUS:85065790261
SN - 1946-6234
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 491
M1 - eaau1167
ER -
