ArticleScientific reports2020
Beta 1 integrin signaling mediates pancreatic ductal adenocarcinoma resistance to MEK inhibition.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- Desmoplasia and therapeutic resistance in pancreatic ductal adenocarcinoma.Cancer letters · 2026Review
- Effect of fibrinogen like protein 1 on cisplatin-resistance in laryngeal carcinoma through targeting integrinβ1 in vivo and in vitro.Discover oncology · 2025Article
- Knowledge Discovery in Databases of Proteomics by Systems Modeling in Translational Research on Pancreatic Cancer.Proteomes · 2025Article
- Proteogenomic analysis reveals Arp 2/3 complex as a common molecular mechanism in high risk pancreatic cysts and pancreatic cancer.Scientific reports · 2025Article
- Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.Cancers · 2024Review
- First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma.International journal of molecular sciences · 2024Article
- A stumbling block in pancreatic cancer treatment: drug resistance signaling networks.Frontiers in cell and developmental biology · 2024Review
- Review
- Review
- Conquering oncogenic KRAS and its bypass mechanisms.Theranostics · 2022Review
- High beta integrin expression is differentially associated with worsened pancreatic ductal adenocarcinoma outcomes.American journal of cancer research · 2022Article
- Integrin β1 Promotes Pancreatic Tumor Growth by Upregulating Kindlin-2 and TGF-β Receptor-2.International journal of molecular sciences · 2021Article
- Implications of prognosis-associated genes in pancreatic tumor metastasis: lessons from global studies in bioinformatics.Cancer metastasis reviews · 2021Review
- Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance.Cancers · 2021Review
- Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer.Biomedicines · 2021Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer. We optimized the culture of pancreatic tumor 3D clusters that utilized Matrigel as a basement membrane mimetic. Pancreatic tumor 3D clusters recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the clusters with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin β1, a mediator of extracellular matrix contact, and found that combined MEK and integrin β1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.
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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.