Evidence map›Paper›PMID 38964731›Full record

ArticleCancer letters2024

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

Michael M Allevato, Sally Trinh, Keiichi Koshizuka, Daniela Nachmanson, Thien-Tu C Nguyen, Yumi Yokoyama, Xingyu Wu, Allen Andres, Zhiyong Wang, Jeramie Watrous and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer letters, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Michael M AllevatoMoores 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.
Sally TrinhMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Keiichi KoshizukaMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Daniela NachmansonBioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
Thien-Tu C NguyenDepartment of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Yumi YokoyamaDracen Pharmaceuticals Inc., 9276 Scranton Rd. Suite 200, San Diego, CA, USA.
Xingyu WuMoores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Allen AndresDepartment of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Zhiyong WangMoores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Jeramie WatrousDepartment of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Alfredo A MolinoloMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Prashant MaliDepartment of Bioengineering, University of California San Diego, La Jolla, CA, USA.
Olivier HarismendyMoores 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.
Mohit JainDepartment of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Robert WildDracen Pharmaceuticals Inc., 9276 Scranton Rd. Suite 200, San Diego, CA, USA.
J Silvio GutkindMoores 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.

Funding

Targeting Signaling Vulnerabilities for Oral Cancer PreventionR01DE026644 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Jorge Silvio Gutkind, SCOTT M LIPPMAN · 2017 to 2026
$4.7M
Signal Transduction by PI3K/mTORR01DE030497 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GUTKIND, JORGE SILVIO, ZHANG, JIN · 2021 to 2025
$2.4M
Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision TherapyR01DE026870 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GUTKIND, JORGE SILVIO · 2018 to 2022
$2.3M
NIDCR NIH HHS R01 DE026644NIDCR NIH HHS R01 DE026870NIDCR NIH HHS R01 DE030497
6 · The paper itself

Abstract

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.

Indexed as

FerroptosisGlutamineHead and Neck NeoplasmsSquamous Cell Carcinoma of Head and NeckXenograft Model Antitumor AssaysAnimalsCell Line, TumorClustered Regularly Interspaced Short Palindromic RepeatsCRISPR-Cas SystemsHumansMiceGlutamineAutophagyFerroptosisGlutamineHead and neck squamous cell carcinomaPoly-unsaturated fatty acidsPrecision medicineTargeted therapy

Identifiers

PMID38964731
PMCPMC12278720

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.