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.
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Targeting mtSTAT3 to modify aberrant oxidative phosphorylation in cancer cells may have contributed to the anticancer effects of OPB-31121, similar to other agents undergoing clinical study that target this cancer cell vulnerability.
“It is of interest to note that targeting of mtSTAT3 to modify aberrant oxidative phosphorylation in cancer cells may have contributed to the anticancer effects of OPB-31121, similar to other agents undergoing clinical study that target this cancer cell vulnerability (Zhang et al., 2019).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Zhang et al., 2019
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“It is of interest to note that targeting of mtSTAT3 to modify aberrant oxidative phosphorylation in cancer cells may have contributed to the anticancer effects of OPB-31121, similar to other agents undergoing clinical study that target this cancer cell vulnerability (Zhang et al., 2019).”
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- 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, M. E., Feng, N., Haun, R., Lan, R., Mackintosh, S. G., Mao, X., Song, X., Zhang, J., Pham, L. V., Lorenzi, P. L., Marszalek, J., Heffernan, T., Draetta, G., Jones, P., Futreal, A., Nomie, K., Wang, L., & Wang, M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- University of Arkansas for Medical Sciences (US)
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Corresponding author
- Zhang, Liang
- Yao, Yixin
- Zhang, Shaojun
- Liu, Yang
- Wang, Linghua
- Wang, Michael
- ORCID
- Zhang, Liang
- Yao, Yixin
- Zhang, Shaojun
- Liu, Yang
- Guo, Hui
- Ahmed, Makhdum
- Bell, Taylor
- Zhang, Hui
- Han, Guangchun
- Lorence, Elizabeth
- Zhou, Shouhao
- Sun, Yuting
- Di Francesco, M. Emilia
- Feng, Ningping
- Haun, Randy
- Lan, Renny
- Mackintosh, Samuel G.
- Song, Xingzhi
- Zhang, Jianhua
- Lorenzi, Philip L.
- Marszalek, Joseph
- Heffernan, Tim
- Draetta, Giulio
- Jones, Philip
- Futreal, Andrew
- Nomie, Krystle
- Wang, Linghua
- Wang, Michael
- Venue
- Science Translational Medicine
- Published
- 2019-05-08
- Volume
- 11
- Issue
- 491
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2943984860
- Cited by
- 233
- References
- 10
- Citations by year
- 2026: 9 · 2025: 28 · 2024: 30 · 2023: 40 · 2022: 47 · 2021: 36 · 2020: 36 · 2019: 6 · 2018: 1
- FWCI
- 9.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P30CA016672, 1S10OD012304, CA016672)
- National Cancer Institute (R21CA202104)
- Cancer Prevention and Research Institute of Texas (RP130397)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- metabolic reprogramming, oxidative phosphorylation, glutaminolysis, mantle cell lymphoma, ibrutinib resistance, BTK inhibitors, IACS-010759, mitochondrial complex I inhibition, cancer metabolism, treatment resistance, relapsed/refractory lymphoma
- MeSH terms
- Exome Sequencing, Adenine, Animals, Mutation, Oxidative Phosphorylation, Piperidines, Pyrazoles, Pyrimidines, Signal Transduction, Drug Resistance, Neoplasm, Lymphoma, Mantle-Cell, Cell Line, Tumor, Mice, DNA Copy Number Variations, Molecular Targeted Therapy, Transcriptome
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