ArticleNature communications2024
Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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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
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- HER2 in Gastric Cancer: A Comprehensive Analysis Combining Meta-Analysis and DCE-MRI Radiomics.Cancer control : journal of the Moffitt Cancer CenterPooled it
- Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.Nature medicine · 2026Trial
- Intracellular Nanopharmacology of Trastuzumab Deruxtecan Reveals Lysosome-Centered Organelle Vulnerabilities in HER2-Positive Breast Cancer Cells.ACS nano medicine · 2026Article
- Feedback activation of MAPK-ERK1/2 signaling causes resistance to trastuzumab-deruxtecan in endometrial cancers.Gynecologic oncology · 2026Article
- Precision Therapeutics in Pancreatic Cancer: Emerging Targeted, Immune, and Antibody-Drug Conjugate Strategies Exemplified by Adagrasib, Dostarlimab, and Trastuzumab Deruxtecan.Journal of clinical medicine · 2026Review
- Pancreatic Cancer: Translating Tumor Biology into Actionability.Cancer discovery · 2026Review
- Single-nucleotide variant profiling in liquid biopsy with RECO-Cas.Science advances · 2026Article
- Pre-clinical efficacy of trastuzumab deruxtecan plus sotorasib inTranslational lung cancer research · 2026Article
- KRAS Inhibition in Pancreatic Ductal Adenocarcinoma.Journal of clinical medicine · 2026Review
- Emerging KRAS G12D inhibitor in the treatment of digestive system tumors: opportunities and challenges.Translational gastroenterology and hepatology · 2026Review
- Evaluation of TRAM@PPF Nanoparticles for Efficacy Against Pancreatic Cancer in Mice Model.International journal of nanomedicine · 2026Article
- Sodium new houttuyfonate affects tumor angiogenesis by suppressing FGF1 expression and the p38/MAPK signaling pathway in pancreatic cancer.Scientific reports · 2025Article
- Quantification of Signal Transduction Pathway Activity in Pancreatic Ductal Adenocarcinoma.International journal of molecular sciences · 2025Article
- Deciphering immune landscapes: an ICD-lncRNA-derived prognostic signature for pancreatic adenocarcinoma.Translational cancer research · 2025Article
- DUSP6 is upregulated in metastasis and influences migration and metabolism in pancreatic cancer cells.Scientific reports · 2025Article
- Construction of lactylation (LA) risk signature in prostate cancer based on 4D fast DIA L-lactated quantitative genomics.Journal of translational medicine · 2025Article
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
- Recent Anti-KRASCancers · 2025Review
- Dynamic Coupling of MAPK Signaling to the Guanine Nucleotide Exchange Factor GEF-H1.OncoTargets and therapy · 2025Review
- Article
Corrections and comments
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Authors and funding
27 authors at 1 institution in 2 countries.
Funding
Abstract
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.
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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.