ArticleThe Journal of clinical investigation2020
TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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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.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- Dexmedetomidine Blocks the ERK Pathway by Inhibiting MAP3K8 to Achieve a Protective Effect in Lung Ischemia/Reperfusion Injury.The Kaohsiung journal of medical sciences · 2025Article
- TPL2 Promotes Gastric Cancer Progression and Chemoresistance Through a Hypoxia-Induced Positive Feedback Loop with PPARδ.International journal of biological sciences · 2025Article
- Article
- IL-1β-activated PI3K/AKT and MEK/ERK pathways coordinately promote induction of partial epithelial-mesenchymal transition.Cell communication and signaling : CCS · 2024Article
- MAP3K8 is a potential therapeutic target in airway epithelial inflammation.Journal of inflammation (London, England) · 2024Article
- IRAK4 Signaling Drives Resistance to Checkpoint Immunotherapy in Pancreatic Ductal Adenocarcinoma.Gastroenterology · 2022Article
- IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies.Current opinion in hematology · 2022Review
- IKBKE-driven TPL2 and MEK1 phosphorylations sustain constitutive ERK1/2 activation in tumor cells.EXCLI journal · 2022Article
- Destabilization of macrophage migration inhibitory factor by 4-IPP reduces NF-κB/P-TEFb complex-mediated c-Myb transcription to suppress osteosarcoma tumourigenesis.Clinical and translational medicine · 2022Article
- The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress.Science translational medicine · 2021Article
- OncogenicCancers · 2021Review
- Phospho-SerCancers · 2021Article
- NF-κB and Pancreatic Cancer; Chapter and Verse.Cancers · 2021Review
- The biological underpinnings of therapeutic resistance in pancreatic cancer.Genes & development · 2021Review
- Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects.World journal of gastroenterology · 2021Review
- Novel role of circRSU1 in the progression of osteoarthritis by adjusting oxidative stress.Theranostics · 2021Article
- Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture.Frontiers in neuroscience · 2021Article
- Article
- Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer.Signal transduction and targeted therapy · 2020Review
- Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
NF-κB transcription factors, driven by the IRAK/IKK cascade, confer treatment resistance in pancreatic ductal adenocarcinoma (PDAC), a cancer characterized by near-universal KRAS mutation. Through reverse-phase protein array and RNA sequencing we discovered that IRAK4 also contributes substantially to MAPK activation in KRAS-mutant PDAC. IRAK4 ablation completely blocked RAS-induced transformation of human and murine cells. Mechanistically, expression of mutant KRAS stimulated an inflammatory, autocrine IL-1β signaling loop that activated IRAK4 and the MAPK pathway. Downstream of IRAK4, we uncovered TPL2 (also known as MAP3K8 or COT) as the essential kinase that propels both MAPK and NF-κB cascades. Inhibition of TPL2 blocked both MAPK and NF-κB signaling, and suppressed KRAS-mutant cell growth. To counter chemotherapy-induced genotoxic stress, PDAC cells upregulated TLR9, which activated prosurvival IRAK4/TPL2 signaling. Accordingly, a TPL2 inhibitor synergized with chemotherapy to curb PDAC growth in vivo. Finally, from TCGA we characterized 2 MAP3K8 point mutations that hyperactivate MAPK and NF-κB cascades by impeding TPL2 protein degradation. Cancer cell lines naturally harboring these MAP3K8 mutations are strikingly sensitive to TPL2 inhibition, underscoring the need to identify these potentially targetable mutations in patients. Overall, our study establishes TPL2 as a promising therapeutic target in RAS- and MAP3K8-mutant cancers and strongly prompts development of TPL2 inhibitors for preclinical and clinical studies.
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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.