Cited by 204Pancreatic and Hepatic Oncology ResearchCancer Immunotherapy and BiomarkersGlycosylation and Glycoproteins Research

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Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

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Sharma, Nikita S., Gupta, Vineet K., Garrido, Vanessa T., Hadad, Roey, Durden, Brittany C., Kesh, Kousik, Giri, Bhuwan, Ferrantella, Anthony, Dudeja, Vikas, Saluja, Ashok, Banerjee, Sulagna·2019·Journal of Clinical Investigation

DOI 10.1172/jci127515PMC PMC6934212

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.

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Authors: Sharma, N. S., Gupta, V. K., Garrido, V. T., Hadad, R., Durden, B. C., Kesh, K., Giri, B., Ferrantella, A., Dudeja, V., Saluja, A., & Banerjee, S.
Affiliations: University of Miami (US)
Corresponding author: Banerjee, Sulagna
ORCID: Sharma, Nikita S.
Gupta, Vineet K.
Garrido, Vanessa T.
Hadad, Roey
Giri, Bhuwan
Ferrantella, Anthony
Dudeja, Vikas
Saluja, Ashok
Banerjee, Sulagna
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2019-12-03
Volume: 130
Issue: 1
Pages: 451-465
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci127515
PMC: PMC6934212
OpenAlex: W2980538229
Cited by: 203
References: 73
Citations by year: 2026: 11 · 2025: 27 · 2024: 22 · 2023: 50 · 2022: 39 · 2021: 37 · 2020: 14 · 2019: 1
FWCI: 9.48
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: NIH (R01-CA170946,to AS, R01-CA124723,to AS, R01- CA184274,to SB)
Katherine and Robert Goodale foundation support (NA)
Minneamrita Therapeutics LLC (NA)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
Keywords: pancreatic ductal adenocarcinoma, hexosamine biosynthetic pathway, 6-diazo-5-oxo-L-norleucine, anti-PD-1 therapy, immune checkpoint inhibitor resistance, hyaluronic acid, extracellular matrix remodeling, tumor microenvironment, CD8+ T cell infiltration, tumor self-renewal, metastasis, glutamine metabolism
MeSH terms: Animals, Diazooxonorleucine, Female, Hexosamines, Humans, Mice, Nude, Neoplasm Metastasis, Neoplasm Proteins, Pancreatic Neoplasms, CD8-Positive T-Lymphocytes, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Programmed Cell Death 1 Receptor

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Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

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