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A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death.

التفاصيل البيبلوغرافية
العنوان: A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death.
المؤلفون: Allevato MM; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Trinh S; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Koshizuka K; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Nachmanson D; Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA., Nguyen TC; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Yokoyama Y; Dracen Pharmaceuticals Inc., 9276 Scranton Rd. Suite 200, San Diego, CA, USA., Wu X; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Andres A; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Wang Z; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Watrous J; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Molinolo AA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Mali P; Department of Bioengineering, University of California San Diego, La Jolla, CA, USA., Harismendy O; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA., Jain M; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA., Wild R; Dracen Pharmaceuticals Inc., 9276 Scranton Rd. Suite 200, San Diego, CA, USA., Gutkind JS; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. Electronic address: sgutkind@health.ucsd.edu.
المصدر: Cancer letters [Cancer Lett] 2024 Aug 28; Vol. 598, pp. 217089. Date of Electronic Publication: 2024 Jul 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
مواضيع طبية MeSH: Glutamine*/metabolism , Squamous Cell Carcinoma of Head and Neck*/genetics , Squamous Cell Carcinoma of Head and Neck*/drug therapy , Squamous Cell Carcinoma of Head and Neck*/metabolism , Squamous Cell Carcinoma of Head and Neck*/pathology , Ferroptosis*/drug effects , Ferroptosis*/genetics , Head and Neck Neoplasms*/genetics , Head and Neck Neoplasms*/drug therapy , Head and Neck Neoplasms*/pathology , Head and Neck Neoplasms*/metabolism , Xenograft Model Antitumor Assays*, Humans ; Animals ; Cell Line, Tumor ; Mice ; Clustered Regularly Interspaced Short Palindromic Repeats ; CRISPR-Cas Systems
مستخلص: Glutamine is a conditionally essential amino acid for the growth and survival of rapidly proliferating cancer cells. Many cancers are addicted to glutamine, and as a result, targeting glutamine metabolism has been explored clinically as a therapeutic approach. Glutamine-catalyzing enzymes are highly expressed in primary and metastatic head and neck squamous cell carcinoma (HNSCC). However, the nature of the glutamine-associated pathways in this aggressive cancer type has not been elucidated. Here, we explored the therapeutic potential of a broad glutamine antagonist, DRP-104 (sirpiglenastat), in HNSCC tumors and aimed at shedding light on glutamine-dependent pathways in this disease. We observed a potent antitumoral effect of sirpiglenastat in HPV- and HPV + HNSCC xenografts. We conducted a whole-genome CRISPR screen and metabolomics analyses to identify mechanisms of sensitivity and resistance to glutamine metabolism blockade. These approaches revealed that glutamine metabolism blockade results in the rapid buildup of polyunsaturated fatty acids (PUFAs) via autophagy nutrient-sensing pathways. Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Wild and Yumi Yokoyama are stockholders of Dracen Pharmaceuticals. Robert Wild reports consulting fees from Dracen Pharmaceuticals. J. Silvio Gutkind reports consulting fees from Domain Pharmaceuticals, Pangea Therapeutics, and io9 and is the founder of Kadima Pharmaceuticals, all unrelated to the current study. Daniela Nachmanson is an employee of TwinStrand Biosciences. Olivier Harismendy is a current employee and shareholder of Zentalis Pharmaceuticals. All other authors declare no potential conflicts of interest.
(Copyright © 2024. Published by Elsevier B.V.)
فهرسة مساهمة: Keywords: Autophagy; Ferroptosis; Glutamine; Head and neck squamous cell carcinoma; Poly-unsaturated fatty acids; Precision medicine; Targeted therapy
المشرفين على المادة: 0RH81L854J (Glutamine)
تواريخ الأحداث: Date Created: 20240704 Date Completed: 20240815 Latest Revision: 20240815
رمز التحديث: 20240816
DOI: 10.1016/j.canlet.2024.217089
PMID: 38964731
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-7980
DOI:10.1016/j.canlet.2024.217089