Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and to identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low-dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal endoplasmic reticulum stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC. Significance: This study demonstrates the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, uncovering a potential therapeutic approach for treating this aggressive disease.
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Glycolysis is a critical downstream effector of oncogenic KRAS signaling in advanced tumors.
“Consistent with our previous findings on the role of glycolysis as a critical downstream effector of oncogenic KRAS signaling in advanced tumors,16,17”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [16]
Glycolysis inhibition can potentially be overcome through compensatory upregulation of oxidative phosphorylation.
“this approach can be potentially overcome through compensatory upregulation of oxidative phosphorylation196”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [196]
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
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“Consistent with our previous findings on the role of glycolysis as a critical down-stream effector of oncogenic KRAS signaling in advanced tumors, 16,17 combined YAP1-ASO and AMG510 treatment led to a significant decrease in several glycolysis enzymes, including hexokinase (HK1 and HK2), enolase…”
Self-citation
- Authors
- Yan, L., Tu, B., Yao, J., Gong, J., Carugo, A., Bristow, C. A., Wang, Q., Zhu, C., Dai, B., Kang, Y., Han, L., Feng, N., Jin, Y., Fleming, J., Heffernan, T. P., Yao, W., & Ying, H.
- Affiliations
- 1Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Ying, Haoqiang
- ORCID
- Venue
- Cancer Research
- Published
- 2021-06-11
- Volume
- 81
- Issue
- 15
- Pages
- 4054-4065
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC8338909
- OpenAlex
- W3170409565
- Cited by
- 48
- References
- 45
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 8 · 2023: 16 · 2022: 9 · 2021: 1
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Cancer Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Center Support (CA016672)
- NCI (R01CA214793, P01CA117969)
- Pancreatic Cancer Action Network (16-70-25-YAO)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, KRAS G12D, MEK inhibition, glucose metabolism, glycolysis, combination therapy, 2-deoxyglucose, endoplasmic reticulum stress, apoptosis, drug resistance
- MeSH terms
- Adenocarcinoma, Animals, Glucose, Humans, Carcinoma, Pancreatic Ductal, Protein Kinase Inhibitors, Mice
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