The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

J, Kim; Cai, Fang; B, Ko; Yang, Chendong; Hm, Lee; Muhammad, Nefertiti; K, Li; Haloul, Mohamed; Gu, W; Faubert, Brandon; Ak, Kaushik; Cai, Lei; Kasiri, Sahba; Marriam, Ummay; Nham, Kien; Girard, Luc; Wang, H; X, Sun; Jd, Minna; Ünsal-Kaçmaz, Keziban; Rj, DeBerardinis

doi:10.1101/2020.04.13.039669

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…KRAS/LKB1 mutant NSCLC depends on GFPT2 and associated pathway components. Azaserine reduces KRAS/LKB1 comutant cell viability (104). Oncogenic KRAS and LKB1 deletion predict aggressive cancer in mice and humans.…”

Section: Kras Mutationsmentioning

confidence: 99%

Targeted Molecular Profiling of Non-small Cell Lung Cancer in India

Dhungel,

Mudagal,

Raj Sharma

et al. 2024

J Adv Immunopharmacol

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: Cancer often rates highly on lists of the world's most hazardous diseases and routinely appears high on lists of the illnesses that people fear the most. Due of its relevance to the subject at hand, this article concentrates on lung cancer rather than other forms of malignancy. Most patients, both those who have never smoked cigarette as well as those who have, are affected by NSCLC, the more common of these two types. The Mesenchymal – Epithelial Transition (MET) protein amplification, EGFR mutations, RET Fusions, and other possible therapeutic targets for the treatment of non-small cell lung cancer are highlighted in this article. The primary aim of this article is to provide a gist of the various mutations and targets' modes of action. It also covers the limits of the medicines that are currently being used to treat certain targets.

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Section: Kras Mutationsmentioning

confidence: 99%

Targeted Molecular Profiling of Non-small Cell Lung Cancer in India

Dhungel,

Mudagal,

Raj Sharma

et al. 2024

J Adv Immunopharmacol

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“…PTMs have gained significant interest in recent omics studies as they directly modulate numerous cancer hallmarks including cell cycle progression, migration and metabolism (12)(13)(14)(15). Previous work showed that metabolic reprogramming toward the hexosamine biosynthesis pathway (HBP), an understudied glucose pathway leading to glycosylation, is associated with poor survival in the lung adenocarcinoma (LUAD) (16,17). The authors reported that this metabolic switch happens earliest in CAFs compared to the malignant cells across tumor compartments (fibroblasts, cancer, immune and endothelial cells).…”

Section: Introductionmentioning

confidence: 99%

Multi-Omics Analysis of Fibroblasts from the Invasive Tumor Edge Reveals that Tumor-Stroma Crosstalk Induces O-glycosylation of the CDK4-pRB Axis

Bouchard

Fjg²,

et al. 2021

Preprint

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The invasive leading edge represents a potential gateway for tumor invasion. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in the activation of key biological pathways depending on their location in the tumor (edge vs core). Here, we highlight phenotypic differences between Tumor-Adjacent-Fibroblasts (TAFs) from the invasive edge and Cancer-Associated Fibroblasts (CAFs) from the tumor core, established from human lung adenocarcinomas. We use an innovative multi-omics approach that includes genomics, proteomics and, O-glycoproteomics to characterize crosstalk between TAFs and cancer cells. Our analysis shows that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the CDK4-pRB axis in the stroma, and indirectly modulates pro-invasive features of cancer cells. In summary, aside from improving the efficacy of CDK4 inhibitors anti-cancer agents, the O-glycoproteome poses a new consideration for important biological processes involved in tumor-stroma crosstalk.

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Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

Peixoto

Freitas

Ferreira

et al. 2021

Preprint

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Bladder cancer constitutes one of the deadliest genitourinary diseases, especially when diagnosed at late stages. These tumours harbour microenvironmental niches characterized by low levels of oxygen (hypoxia) and limited glucose supply due to poor vascularization. However, the synergic contribution of these features to disease development is poorly understood. Here, we demonstrated that cells with distinct histopathological and molecular backgrounds responded similarly to such stimuli. Cancer cells arrested proliferation, significantly increased invasive capacity in vitro and enhanced tolerance to cisplatin-based chemotherapy. Reoxygenation and access to glucose restored basal proliferation and invasion levels without triggering stress-induced apoptosis, denoting significant cellular plasticity in adapting to microenvironmental cues. Whole transcriptomics showed major molecular reprogramming, supporting main functional alterations. Metabolomics evidenced fatty acids β-oxidation as main bioenergetic pathway rather than anaerobic glycolysis generally adopted by hypoxic cells. Joint pathway analysis also suggested relevant alterations in mucin-type O-glycan biosynthesis. Glycomics confirmed a major antagonization of O-glycosylation pathways, leading to simple cell glycophenotypes characterized by the accumulation of immature short-chain O-glycans such as Tn and STn antigens at the cell surface. Glycoengineered models reflecting simple cell glycophenotypes were developed and functional studies in vitro and in vivo showed that Tn and STn overexpression decreased proliferation and promoted chemoresistance, reinforcing their close link with tumour aggressiveness. Collectively, we have demonstrated that hypoxia and glucose deprivation trigger more aggressive cell behaviours, in what appears to be an escape mechanism from microenvironmental stress. We propose that, altered glycosylation may be used to target these subpopulations, paving the way for precision oncology.

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The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

Cited by 3 publications

References 46 publications

Targeted Molecular Profiling of Non-small Cell Lung Cancer in India

Targeted Molecular Profiling of Non-small Cell Lung Cancer in India

Multi-Omics Analysis of Fibroblasts from the Invasive Tumor Edge Reveals that Tumor-Stroma Crosstalk Induces O-glycosylation of the CDK4-pRB Axis

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

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