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

Liang Zhang; Yixin Yao; Shaojun Zhang; Yang Liu; Hui Guo; Makhdum Ahmed; Taylor Bell; Hui Zhang; Guangchun Han; Elizabeth Lorence; Maria Badillo; Shouhao Zhou; Yuting Sun; M. Emilia Di Francesco; Ningping Feng; Randy Haun; Renny Lan; Samuel G. MacKintosh; Xizeng Mao; Xingzhi Song; Jianhua Zhang; Lan V. Pham; Philip L. Lorenzi; Joseph Marszalek; Tim Heffernan; Giulio Draetta; Philip Jones; Andrew Futreal; Krystle Nomie; Linghua Wang; Michael Wang

doi:10.1126/scitranslmed.aau1167

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

Liang Zhang, Yixin Yao, Shaojun Zhang, Yang Liu, Hui Guo, Makhdum Ahmed, Taylor Bell, Hui Zhang, Guangchun Han, Elizabeth Lorence, Maria Badillo, Shouhao Zhou, Yuting Sun, M. Emilia Di Francesco, Ningping Feng, Randy Haun, Renny Lan, Samuel G. MacKintosh, Xizeng Mao, Xingzhi SongJianhua Zhang, Lan V. Pham, Philip L. Lorenzi, Joseph Marszalek, Tim Heffernan, Giulio Draetta, Philip Jones, Andrew Futreal, Krystle Nomie, Linghua Wang, Michael Wang

Research output: Contribution to journal › Article › peer-review

150 Scopus citations

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.

Original language	English (US)
Article number	eaau1167
Journal	Science translational medicine
Volume	11
Issue number	491
DOIs	https://doi.org/10.1126/scitranslmed.aau1167
State	Published - 2019

ASJC Scopus subject areas

General Medicine

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Bioinformatics Shared Resource
Biostatistics Resource Group
Functional Proteomics Reverse Phase Protein Array Core
Metabolomics Facility

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10.1126/scitranslmed.aau1167

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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, M. E., Feng, N., Haun, R., Lan, R., MacKintosh, S. G., Mao, X., ... Wang, M. (2019). Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma. Science translational medicine, 11(491), Article eaau1167. https://doi.org/10.1126/scitranslmed.aau1167

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, Heffernan, T, Draetta, G, Jones, P, Futreal, A, Nomie, K, Wang, L & Wang, M 2019, 'Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma', Science translational medicine, vol. 11, no. 491, eaau1167. https://doi.org/10.1126/scitranslmed.aau1167

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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.",

author = "Liang Zhang and Yixin Yao and Shaojun Zhang and Yang Liu and Hui Guo and Makhdum Ahmed and Taylor Bell and Hui Zhang and Guangchun Han and Elizabeth Lorence and Maria Badillo and Shouhao Zhou and Yuting Sun and {Di Francesco}, {M. Emilia} and Ningping Feng and Randy Haun and Renny Lan and MacKintosh, {Samuel G.} and Xizeng Mao and Xingzhi Song and Jianhua Zhang and Pham, {Lan V.} and Lorenzi, {Philip L.} and Joseph Marszalek and Tim Heffernan and Giulio Draetta and Philip Jones and Andrew Futreal and Krystle Nomie and Linghua Wang and Michael Wang",

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doi = "10.1126/scitranslmed.aau1167",

language = "English (US)",

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journal = "Science translational medicine",

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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

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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