The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer

Kim, Jiyeon; Lee, Hyun Min; Cai, Feng; Ko, Bookyung; Yang, Chendong; Lieu, Elizabeth L.; Muhammad, Nefertiti; Rhyne, Shawn; Li, Kailong; Haloul, Mohamed; Gu, Wen; Faubert, Brandon; Kaushik, Akash; Cai, Ling; Kasiri, Sahba; Marriam, Ummay; Nham, Kien; Girard, Luc; Wang, Hui; Sun, Xiankai; Kim, James; Minna, John D.; Ünsal-Kaçmaz, Keziban; DeBerardinis, Ralph J.

doi:10.1038/s42255-020-00316-0

Cited by 90 publications

(105 citation statements)

References 50 publications

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“…UTP is critical for protein glycosylation by serving as a glycosylation substrate sub-fraction. It is reported that protein glycosylation level is generally elevated in various malignancies and has been identified as a hallmark of cancer (61). As an abundant post-translational modification of protein, glycosylation takes part in sustaining cancer cell growth and proliferation (62)(63)(64)(65)(66)(67)(68)(69).…”

Section: Dysfunction Of Pyrimidine Metabolism In Cancersmentioning

confidence: 99%

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Wang

Cui

et al. 2021

Front. Oncol.

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Metabolic rewiring is considered as a primary feature of cancer. Malignant cells reprogram metabolism pathway in response to various intrinsic and extrinsic drawback to fuel cell survival and growth. Among the complex metabolic pathways, pyrimidine biosynthesis is conserved in all living organism and is necessary to maintain cellular fundamental function (i.e. DNA and RNA biosynthesis). A wealth of evidence has demonstrated that dysfunction of pyrimidine metabolism is closely related to cancer progression and numerous drugs targeting pyrimidine metabolism have been approved for multiple types of cancer. However, the non-negligible side effects and limited efficacy warrants a better strategy for negating pyrimidine metabolism in cancer. In recent years, increased studies have evidenced the interplay of oncogenic signaling and pyrimidine synthesis in tumorigenesis. Here, we review the recent conceptual advances on pyrimidine metabolism, especially dihydroorotate dehydrogenase (DHODH), in the framework of precision oncology medicine and prospect how this would guide the development of new drug precisely targeting the pyrimidine metabolism in cancer.

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Section: Dysfunction Of Pyrimidine Metabolism In Cancersmentioning

confidence: 99%

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Wang

Cui

et al. 2021

Front. Oncol.

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“…Besides, transsulfuration‐mediated cysteine synthesis is critical for promoting tumour growth in vivo 38 . The hexosamine biosynthetic pathway is a shunt pathway of glycolysis and is a metabolic node in cancer cells 39 . Studies have shown that the up‐regulation of the hexosamine biosynthetic pathway is related to tumour survival and chemotherapy resistance 40 .…”

Section: Discussionmentioning

confidence: 99%

“… 38 The hexosamine biosynthetic pathway is a shunt pathway of glycolysis and is a metabolic node in cancer cells. 39 Studies have shown that the up‐regulation of the hexosamine biosynthetic pathway is related to tumour survival and chemotherapy resistance. 40 Inhibiting the biosynthetic pathway of hexosamine can have a significant therapeutic effect on patients with acute myeloid leukaemia.…”

Section: Discussionmentioning

confidence: 99%

Signature based on metabolic‐related gene pairs can predict overall survival of osteosarcoma patients

Zhang

Yuan

et al. 2021

Cancer Medicine

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Background Osteosarcoma is a tumour of malignant origin in children and adolescents. Recent progression indicates that it is necessary to develop new therapies to improve the patient's prognosis rather than strengthen anti‐tumour chemotherapy. Researchers recently realised that cancer is a kind of disease with a metabolic disorder, and metabolic reprogramming is becoming a new cancer hallmark. Hence, our study's primary purpose is to explore the value of genes related to osteosarcoma metabolism. Methods From public databases, three osteosarcoma datasets with adequate clinical information were obtained. Besides, the IMvigor dataset through the ‘IMvigor’ package as a supplement was downloaded, the metabolic‐related genes were identified, and these genes were used to construct the metabolic‐related gene pairs (MRGP). Based on the prognosis‐related MRGP, two molecular subtypes were identified. There are significant differences in the metabolic characteristics between the two molecular subtypes. Subsequently, the MRGP signature is constructed using the least absolute shrinkage and selection operator regression method. Finally, use SubMap analysis to evaluate the response of patients in the MRPG signature group to immunotherapy. Results The MRGP signature can reliably predict overall survival in patients with osteosarcoma. The MRGP signature is also associated with osteosarcoma patients’ metastatic status and can be used for subsequent risk classification of metastatic patients. The immunotherapy is more likely to benefit the patients in the MRGP low‐risk group. Conclusion Metabolic‐related gene pairs signature can assess the prognosis of patients with osteosarcoma.

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“…Finally, we need to evaluate how silibinin interacts with the BBB to impede transmigration of brain metastasisinitiating cells and/or to regulate the metabolism and brain accumulation of targeted therapies. The unraveling of an unforeseen, selective vulnerability of silibinin-treated tumor cells to the hexosamine biosynthesis pathway inhibitor azaserine using genomically edited isogenic models might exemplify how to exploit the therapeutic usage of silibinin in combination with certain targetable weaknesses in specific subtypes of lung cancer (e.g., KRAS/STK11 co-mutant tumors with dependence on the hexosamine biosynthesis pathway through GFPT2 [104]). Using silibinin as a lead structure to guide development, it would be possible to use synthetic chemistry approaches to generate a battery of silibinin derivatives with enhanced radiosensitizing capacity and augmented brain targeting.…”

Section: Silibinin and Lung Cancer: The Past Present And Future (A Corollary)mentioning

confidence: 99%

Lung Cancer Management with Silibinin: A Historical and Translational Perspective

et al. 2021

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The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.

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The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer

Cited by 90 publications

References 50 publications

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Signature based on metabolic‐related gene pairs can predict overall survival of osteosarcoma patients

Lung Cancer Management with Silibinin: A Historical and Translational Perspective

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