ArticleNature medicine2019
Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.
Erratum issued Registry-linked trialAbstract read
In one paragraph
Article in Nature medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT02704156 (Stereotactic Body Radiation Therapy Plus Pembrolizumab and Trametinib vs. Stereotactic Body Radiation Therapy Plus Gemcitabine for Locally Recurrent Pancreatic Cancer After Surgical Resection), which is not on this map. Cited by 436 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
436citing papers in PubMed, 2 pooled it
70.9field-weighted citation impact, top 1% of its field
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.
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.
Stereotactic Body Radiation Therapy Plus Pembrolizumab and Trametinib vs. Stereotactic Body Radiation Therapy Plus Gemcitabine for Locally Recurrent Pancreatic Cancer After Surgical Resection: an Open-label, Randomized, Controlled, Phase 2 Trial
Who cites it
436 citing papers in PubMed, 2 syntheses or guidelines pooled it, 699 citations in OpenAlex.
- Signaling pathway mechanisms in pancreatic ductal adenocarcinoma tumor microenvironment and emerging targeting strategies for improved prognosis.Oncology reviews · 2026Pooled it
- The safety and efficacy of binimetinib for lung cancer: a systematic review.BMC pulmonary medicine · 2024Pooled it
- Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer.JCO precision oncology · 2025Trial
- Raf kinase inhibitor protein combined with phosphorylated extracellular signal-regulated kinase offers valuable prognosis in gastrointestinal stromal tumor.World journal of gastroenterology · 2023Trial
- A Phase II Open-Label Trial of Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS-Mutant Non-Small Cell Lung Cancer.The oncologist · 2023Trial
- Transcriptomic profiling reveals autophagy-associated programs and prognostic biomarkers in anoikis-resistant pancreatic cancer cells.BMC cancer · 2026Article
- Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth inScience advances · 2026Article
- ZBED6 deficiency drives pathological cardiac hypertrophy through MEOX1-ERK1/2-dependent autophagy dysfunction.PLoS genetics · 2026Article
- Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.Genes & development · 2026Review
- Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.British journal of cancer · 2026Article
- Review
- Mutant KRAS-mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Autophagy modulation in cancer.Nature reviews. Drug discovery · 2026Review
- Autophagy Orchestrates Anti-Tumor Immunity to Enhance Chemosensitivity via the FBXW2/C/EBPβ/TIMP-2 Axis in Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.Cancer research · 2026Article
- Cancer-Associated Fibroblast-Derived Sphingosine-1-Phosphate Activates a MALL-SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Small-molecule autophagy modulators: Mechanisms, therapeutic potential, and development challenges in pathological settings.Fundamental research · 2026Review
- Review
- The Lysosome-Cathepsin Axis in Pancreatic Cancer: Mechanisms of Stromal Remodeling, Immune Evasion, and Therapy Resistance.Biomolecules · 2026Review
- Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.bioRxiv : the preprint server for biology · 2026Article
376 more citing papers are in PubMed but not listed here.
Corrections and comments
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- Erratum issued
Authors and funding
31 authors at 10 institutions in 1 country.
Kirsten L BryantLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0003-4026-0942
Clint A StalneckerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-0570-4416
Daniel ZeitouniLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Jennifer E KlompLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Sen PengCancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
Andrey P TikunovBiomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Venugopal GundaEppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
Mariaelena PierobonCenter for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
Andrew M WatersLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-6058-5878
Samuel D GeorgeLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Garima TomarLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Björn PapkeLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-8156-7508
G Aaron HobbsLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-4751-9681
Liang YanDepartment of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Tikvah K HayesCurriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Nathaniel DiehlCurriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Gennifer D GoodeEppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
Nina V ChaikaEppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
Yingxue WangSarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA.
Guo-Fang ZhangSarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA.
Agnieszka K WitkiewiczCenter for Personalized Medicine, Roswell Park Cancer Center, Buffalo, NY, USA.
Erik S KnudsenDepartment of Molecular and Cell Biology, Roswell Park Cancer Center, Buffalo, NY, USA.
Emanuel F PetricoinCenter for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
Pankaj K SinghEppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
Jeffrey M MacdonaldBiomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nhan L TranDepartment of Cancer Biology, Mayo Clinic, Phoenix, AZ, USA.
Costas A LyssiotisDepartment of Molecular and Integrative Physiology; Department of Internal Medicine, Division of Gastroenterology and University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-9309-6141
Haoqiang YingDepartment of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Alec C KimmelmanPerlmutter Cancer Center, NYU Langone Medical Center, New York City, NY, USA.
Adrienne D CoxLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Channing J DerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cjder@med.unc.edu.ORCID http://orcid.org/0000-0002-7751-2747
University of North Carolina at Chapel Hill · USUniversity of Nebraska Medical Center · USDuke University · USGeorge Mason University · USRoswell Park Comprehensive Cancer Center · USThe University of Texas MD Anderson Cancer Center · USMayo Clinic in Florida · USNYU Langone Health · USTranslational Genomics Research Institute · USUniversity of Michigan · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MVirology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5MUNMC/EPPLEY CANCER CENTER SUPPORT GRANTP30CA036727 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI Apar Kishor Ganti · 1985 to 2026
$55.0MThe RAS and P13K Pathways in Pancreatic AdenocarcinomaP01CA117969 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DEPINHO, RONALD ANTHONY · 2006 to 2025
$41.7MUNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Melissa A. Troester · 2001 to 2026
$36.3MIntegrated Training in Cancer Model SystemsT32CA009156 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1985 to 2020
$19.7MTissue CoreP50CA127297 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI HOLLINGSWORTH, MICHAEL A. · 2008 to 2018
$17.1MWashington University SPORE in Pancreatic CancerP50CA196510 · NCI · WASHINGTON UNIVERSITY · PI FIELDS, RYAN C · 2016 to 2020
$10.9MProject 4: The role of codon bias in RAS tumorigenesisP01CA203657 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI COUNTER, CHRISTOPHER M · 2016 to 2020
$7.9MIdentifying Metabolic Dependencies of Pancreatic CancersR35CA232124 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI KIMMELMAN, ALEC · 2018 to 2024
$6.5MTargeting undruggable RAS for cancer treatmentR35CA232113 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 2018 to 2024
$6.3MBIOLOGICAL ACTIVITY OF RAS ONCOGENESR01CA042978 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1986 to 2017
$5.9MNCI NIH HHS F30 CA243253NCI NIH HHS F32 CA200313NCI NIH HHS F32 CA232529NCI NIH HHS F32 CA239328NCI NIH HHS P01 CA117969NCI NIH HHS P01 CA203657NCI NIH HHS P30 CA016086NCI NIH HHS P30 CA016672NCI NIH HHS P30 CA036727NCI NIH HHS P50 CA127297NCI NIH HHS P50 CA196510NCI NIH HHS R01 CA042978NCI NIH HHS R01 CA157490NCI NIH HHS R01 CA163649NCI NIH HHS R01 CA175747NCI NIH HHS R01 CA188048NCI NIH HHS R01 CA210439NCI NIH HHS R01 CA216853NCI NIH HHS R35 CA232113NCI NIH HHS R35 CA232124NCI NIH HHS T32 CA009156NCI NIH HHS T32 CA071341NCI NIH HHS U01 CA199235NIEHS NIH HHS P30 ES010126NIGMS NIH HHS R01 GM095567
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
Indexed as
AutophagyMAP Kinase Signaling SystemAnimalsCell Line, TumorCell ProliferationChloroquineDrug SynergismHEK293 CellsHumansMiceMitochondriaMutationPancreatic NeoplasmsProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)ChloroquineKRAS protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)
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Read underepoch 390
Registered trials
NCT02704156ClinicalTrials.gov
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.