ArticleGastroenterology2022
Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer.
Article in Gastroenterology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 2 of them syntheses that pooled it.
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Who cites it
114 citing papers in PubMed, 2 syntheses or guidelines pooled it, 151 citations in OpenAlex.
- Signaling pathway mechanisms in pancreatic ductal adenocarcinoma tumor microenvironment and emerging targeting strategies for improved prognosis.Oncology reviews · 2026Pooled it
- A Meta-Analysis Approach to Gene Regulatory Network Inference Identifies Key Regulators of Cardiovascular Diseases.International journal of molecular sciences · 2024Pooled it
- Spatial interactions of immune cells as potential predictors to efficacy of toripalimab plus chemotherapy in locally advanced or metastatic pancreatic ductal adenocarcinoma: a phase Ib/II trial.Signal transduction and targeted therapy · 2024Trial
- Trial
- Programmed cell death in inflammation: interactions and holistic perspective.Cellular & molecular immunology · 2026Review
- SNU523 Inhibits Pancreatic Cancer through the Dual Suppression of STAT3 and MEK Signaling Pathways.ACS omega · 2026Article
- Nanotechnology-enabled precision targeting of lung cancer stem cells: Recent developments and therapeutic implications.Stem cell reviews and reports · 2026Review
- Review
- Multi-omics characterization of a GPRC5AJournal of translational medicine · 2026Article
- Adaptive resistance in cancer immunotherapy.Cellular & molecular immunology · 2026Review
- From paradox to target: IFN-β hijacks MEK signaling to drive a cell death-evading dormant phenotype in colorectal cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Immune-driven stromal inflammation in pancreatic cancer within a microfluidic platform.Biofabrication · 2026Article
- IL1RAP-expressing myeloid-stromal networks represent a therapeutic vulnerability to improve chemoimmunotherapy sensitivity in pancreatic cancer.JCI insight · 2026Article
- PI3K and MAPK Signaling Nodes Serve as Divergent Drivers of Phenotypic Plasticity in Cancer-Associated Fibroblasts in Colorectal Cancer.Cancer research · 2026Article
- CAF-derived PTGDS drives pancreatic cancer neuroendocrine differentiation and chemoresistance via PAQR9-MAPK.Oncogenesis · 2026Article
- Beyond suppression: the paradox of JAK inhibitors as amplifiers of cancer immunotherapy.Nature reviews. Immunology · 2026Review
- Bidirectional crosstalk between cancer-associated fibroblasts and tumor immunity: shaping the microenvironment and response to immune checkpoint therapy.Experimental hematology & oncology · 2026Review
- DB-2B, a Novel and Selective STAT3 Inhibitor Inhibits Colorectal Cancer Progression In Vitro and In Vivo.Biomolecules · 2026Article
- DEC1 Deficiency Attenuates Breast Cancer-Induced Osteolytic Destruction by Suppression of Cancer-Associated Fibroblast Differentiation.Cancer medicine · 2026Article
- A tumor microenvironment integrated (TMI) staging system for pancreatic ductal adenocarcinoma based on cancer-associated fibroblast and molecular consensus signatures.Discover oncology · 2026Article
54 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsWe have shown that reciprocally activated rat sarcoma (RAS)/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine whether MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC.
methodsCAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i (ruxolitinib)-treated vs vehicle-treated Ptf1a
resultsMEKi+STAT3i attenuates Il6/Cxcl1-expressing proinflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of cluster of differentiation 8
conclusionsCombined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC.
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Registered trials
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.