Journal
CANCER CELL
Volume 33, Issue 5, Pages 905-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.04.002
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Funding
- CTSI at the UCLA David Geffen School of Medicine
- KL2 Translational Science Award at the UCLA David Geffen School of Medicine [KL2TR000122, UL1TR000124]
- Department of Defense LCRP grant [W81XWH-13-1-0459]
- American Cancer Society [RSG-16-234-01-TBG]
- American Lung Association
- Addario Lung Cancer Foundation
- STOP Cancer Foundation
- NIH T32 training grant through the UCLA David Geffen School of Medicine [HL072752]
- NCI/NIH [P01 CA168585]
- American Cancer Society Research Scholar award [RSG-12-257-01-TBE]
- National Center for Advancing Translational Sciences UCLA CSTI grant [UL1TR000124]
- NATIONAL CANCER INSTITUTE [P30CA016042, P01CA168585] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL072752] Funding Source: NIH RePORTER
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Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3 alpha/beta signaling pathway, which upregulates glutaminolysis. Phospho-GSK3 alpha/beta protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance. In addition, we identified a conserved metabolic signature in a broad spectrum of hypermetabolic human tumors that may be predictive of patient outcome and response to combined metabolic therapies targeting mTOR and glutaminase.
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