ArticleGastroenterology2017
Inhibition of Aurora Kinase A Induces Necroptosis in Pancreatic Carcinoma.
Article in Gastroenterology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers, 1 of them a synthesis that pooled it.
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Who cites it
123 citing papers in PubMed, 1 synthesis or guideline pooled it, 191 citations in OpenAlex.
- Necroptosis in pancreatic cancer: Molecular mechanisms and therapeutic implications.Apoptosis : an international journal on programmed cell death · 2026Pooled it
- Necroptosis-related diseases are regulated by the unfolded protein response during endoplasmic reticulum stress.Genes & diseases · 2027Review
- Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- DAMP signaling networks: from receptors to diverse pathophysiological functions.Journal of advanced research · 2026Review
- Programmed cell death in lung cancer: mechanisms, immune responses, and therapeutics.Apoptosis : an international journal on programmed cell death · 2026Review
- Development and prognostic evaluation of an integrative programmed cell death index in pancreatic cancer based on multiple cell death modalities.Discover oncology · 2026Article
- Splice-switching ASOs targeting the AURKA 5' UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer.Molecular cell · 2026Article
- Aurora kinase B as a therapeutic target in HPV-induced cervical cancer: mechanisms and future perspectives.Frontiers in oncology · 2026Review
- Unraveling the molecular landscape of pancreatic cancer: a systems biology approach to identify therapeutic targets.Discover oncology · 2025Article
- Mebendazole induces ZBP-1 mediated PANoptosis of acute myeloid leukemia cells by targeting TUBA1A and exerts antileukemia effect.Journal of advanced research · 2025Article
- Article
- PANoptosis: potential new targets and therapeutic prospects in digestive diseases.Apoptosis : an international journal on programmed cell death · 2025Review
- CDC26 facilitates ferroptosis through SLC7A11 degradation and cell cycle arrest.Clinical and experimental medicine · 2025Article
- Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Salecan Suppresses Pancreatic Cancer Progression by Promoting Necroptosis via the RIPK1/MLKL Pathway.Nutrients · 2025Article
- Current progress in targeting mitotic kinases in PDAC.RSC medicinal chemistry · 2025Review
- Palmatine inhibits colorectal cancer proliferation and metastasis by regulating miR-363-3p/AURKA axis.Human cell · 2025Article
- AURKA promotes angiogenesis in uveal melanoma via activation of the JAK2/STAT3/VEGFA signaling pathway.Cancer cell international · 2025Article
- CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer.Nature communications · 2025Article
- Novel Machine Learning Approaches Revolutionize Pancreatic Malignancy Prognosis: Exploring Programed Cell Death.Mediators of inflammation · 2025Article
63 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsInduction of nonapoptotic cell death could be an approach to eliminate apoptosis-resistant tumors. We investigated necroptosis-based therapies in mouse models of pancreatic ductal adenocarcinoma cancer (PDAC).
methodsWe screened 273 commercially available kinase inhibitors for cytotoxicity against a human PDAC cell line (PANC1). We evaluated the ability of the aurora kinase inhibitor CCT137690 to stimulate necroptosis in PDAC cell lines (PANC1, PANC2.03, CFPAC1, MiaPaCa2, BxPc3, and PANC02) and the HEK293 cell line, measuring loss of plasma membrane integrity, gain in cell volume, swollen organelles, and cytoplasmic vacuoles. We tested the effects of CCT137690 in colon formation assays, and the effects of the necroptosis (necrostatin-1 and necrosulfonamide), apoptosis, autophagy, and ferroptosis inhibitors. We derived cells from tumors that developed in Pdx1-Cre;K-Ras
resultsCCT137690 induced necrosis-like death in PDAC cell lines and reduced colony formation; these effects required RIPK1, RIPK3, and MLKL, as well as inhibition of aurora kinase A (AURKA). AURKA interacted directly with RIPK1 and RIPK3 to reduce necrosome activation. AURKA-mediated phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at serine 9 inhibited activation of the RIPK3 and MLKL necrosome. Mutations in AURKA (D274A) or GSK3β (S9A), or pharmacologic inhibitors of RIPK1 signaling via RIPK3 and MLKL, reduced the cytotoxic activity of CCT137690 in PDAC cells. Oral administration of CCT137690 induced necroptosis and immunogenic cell death in subcutaneous and orthotopic tumors in mice, and reduced tumor growth and tumor cell phosphorylation of AURKA and GSK3β. CCT137690 increased survival times of mice with orthotopic KPC PDACs and reduced tumor growth, stroma, and metastasis. Increased expression of AURKA and GSK3β mRNAs associated with shorter survival times of patients with pancreatic cancer.
conclusionsWe identified the aurora kinase inhibitor CCT137690 as an agent that induces necrosis-like death in PDAC cells, via RIPK1, RIPK3, and MLKL. CCT137690 slowed growth of orthotopic tumors from PDAC cells in mice, and expression of AURKA and GSK3β associate with patient survival times. AURKA might be targeted for treatment of 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.