Evidence map›Paper›PMID 41000736›Full record

ArticlebioRxiv : the preprint server for biology2025

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.

Alica K Beutel, Sabrina Calderon, Ethan Nghiem, Kevin Gulay, Leonor P S Santana, Eleni Zimmer, Rima Singh, Cecily Anaraki, Natalie Yousefian, Chantal Allgöwer and 16 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

26 authors.

Alica K BeutelDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Sabrina CalderonDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Ethan NghiemDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Kevin GulayDepartment of Surgery, University of California San Diego, La Jolla, USA.
Leonor P S SantanaWest of Scotland HPB Unit, Glasgow Royal Infirmary, Glasgow G61 1QH, UK.
Eleni ZimmerInstitute of Molecular Oncology and Stem Cell Biology, University Hospital Ulm, Ulm, Germany.
Rima SinghDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Cecily AnarakiDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Natalie YousefianDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Chantal AllgöwerInstitute of Molecular Oncology and Stem Cell Biology, University Hospital Ulm, Ulm, Germany.
Gregory TongDepartment of Pharmaceutical Sciences University of California Irvine, Irvine, USA.
Cameron GellerDepartment of Developmental and Cell Biology University of California Irvine, Irvine, USA.
Alina ChaoDepartment of Biological Chemistry University of California Irvine, Irvine, USA.
Dennis JuarezDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Thomas SeufferleinDepartment of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
Alexander MuirBen May Department for Cancer Research University of Chicago, Chicago, USA.
Cholsoon JangDepartment of Biological Chemistry University of California Irvine, Irvine, USA.
Aimee L EdingerDepartment of Pharmaceutical Sciences University of California Irvine, Irvine, USA.
Marcus SeldinDepartment of Biological Chemistry University of California Irvine, Irvine, USA.
Thomas F MartinezDepartment of Pharmaceutical Sciences University of California Irvine, Irvine, USA.
Alexander KlegerInstitute of Molecular Oncology and Stem Cell Biology, University Hospital Ulm, Ulm, Germany.
David K ChangWest of Scotland HPB Unit, Glasgow Royal Infirmary, Glasgow G61 1QH, UK.
Herve TiriacDepartment of Surgery, University of California San Diego, La Jolla, USA.
Jennifer B ValerinChao Family Comprehensive Cancer Center, University of California Irvine, USA.
David A FrumanDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.
Christopher J HalbrookDepartment of Molecular Biology and Biochemistry University of California Irvine, Irvine, USA.

Funding

Univ.of Calif., Irvine Cancer Center Support GrantP30CA062203 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI RICHARD A. VAN ETTEN · 1994 to 2026
$57.9M
CARCINOGENESIST32CA009054 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI EDINGER, AIMEE L, FRUMAN, DAVID ALEXANDER · 1985 to 2025
$8.6M
Targeting Metabolic Crosstalk in Pancreatic CancerR37CA283575 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Christopher J. Halbrook · 2024 to 2026
$1.3M
Targeting nutrient microenvironment imprinted therapy resistance in pancreatic cancerR01CA276461 · NCI · UNIVERSITY OF CHICAGO · PI Alexander Muir · 2024 to 2026
$1.2M
Disrupting macrophage metabolism to reduce immunosuppression and enhance therapy in pancreatic cancerR00CA241357 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI HALBROOK, CHRISTOPHER J. · 2020 to 2022
$778k
The Roles of a Novel Microprotein in Wound Healing and CancerK01CA249038 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI MARTINEZ, THOMAS FARID · 2021 to 2025
$688k
NCI NIH HHS K01 CA249038NCI NIH HHS P30 CA062203NCI NIH HHS R00 CA241357NCI NIH HHS R01 CA276461NCI NIH HHS R37 CA283575NCI NIH HHS T32 CA009054
6 · The paper itself

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy. However, resistance remains a major hurdle in clinical care. Resistance can arise from microenvironmental metabolites or through direct metabolic reprogramming of pancreatic cancer cells. Here, we generated PDAC models of acquired gemcitabine resistance to determine the relationship between these mechanisms. We observed that physiological levels of exogenous pyrimidines have a diminished ability to impact gemcitabine response in PDAC cells with acquired resistance. This occurs as the metabolic reprogramming of PDAC cells in response to gemcitabine treatment forces a suppression of the pyrimidine salvage pathway. Importantly, this metabolic rewiring renders gemcitabine-resistant PDAC cells highly susceptible to inhibition of the rate limiting enzyme of the mevalonate biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), using statins. Notably, statin treatment inhibits the growth of gemcitabine-resistant tumors in immunocompetent mouse models. Through metabolite rescue experiments, we identified geranylgeranyl pyrophosphate as the critical metabolite lost during statin treatment, resulting in reduced protein geranylation in PDAC cells. Finally, as downregulation of the

Identifiers

PMID41000736
PMCPMC12458164

What Socratic holds

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Registered trials

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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 Socratic graph.