ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 134 citations in OpenAlex.
- Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non-Small Cell Lung Cancer Harboring EGFR Mutation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
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- Ferroptosis in Cancer and Inflammatory Diseases: Mechanisms and Therapeutic Implications.MedComm · 2025Review
- Downregulation of ferroptosis-related Genes can regulate the invasion and migration of osteosarcoma cells.Scientific reports · 2025Article
- Epithelial-mesenchymal transition (EMT) and its role in acquired epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) chemoresistance in non-small cell lung cancer (NSCLC).Cancer pathogenesis and therapy · 2025Review
- Targeting Ferroptosis: Small-molecule Inducers as Novel Anticancer Agents.Anti-cancer agents in medicinal chemistry · 2025Review
- The impact of 9-azaglycophymine and phenylguanidine derivatives on the proliferation of various breast cancer cell lines in vitro and in vivo.Scientific reports · 2024Article
- Ferroptosis-related gene signature for predicting prognosis and identifying potential therapeutic drug in EGFR wild-type lung adenocarcinoma.Communications biology · 2024Article
- Programmed cell death and melatonin: A comprehensive review.Functional & integrative genomics · 2024Review
- Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.Cancer cell international · 2024Review
- Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations.Oncology letters · 2024Article
- Ferroptosis: principles and significance in health and disease.Journal of hematology & oncology · 2024Review
- Role of oxidative stress-induced ferroptosis in cancer therapy.Journal of cellular and molecular medicine · 2024Review
- Insight into Iron, Oxidative Stress and Ferroptosis: Therapy Targets for Approaching Anticancer Strategies.Cancers · 2024Review
- Role of ferroptosis in chronic kidney disease.Cell communication and signaling : CCS · 2024Review
- Ferroptosis: Emerging mechanisms, biological function, and therapeutic potential in cancer and inflammation.Cell death discovery · 2024Review
- Methionine enkephalin (MENK) protected macrophages from ferroptosis by downregulating HMOX1 and ferritin.Proteome science · 2024Article
- Integrating single-cell transcriptomics to reveal the ferroptosis regulators in the tumor microenvironment that contribute to bladder urothelial carcinoma progression and immunotherapy.Frontiers in immunology · 2024Article
- Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds.International journal of molecular sciences · 2023Review
- Emerging roles and therapeutic potentials of ferroptosis: from the perspective of 11 human body organ systems.Molecular and cellular biochemistry · 2023Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
purposeResults of multiple clinical trials suggest that EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) exhibit negative effects on platinum-based chemotherapy in patients with lung cancer with wild-type (WT) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with WT EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon. EXPERIMENTAL
designWe investigated the effects of TKIs and cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism by which EGFR signaling pathway is involved in CID. Finally, on the basis of the identified mechanism, we tested the combinational effects of cisplatin plus suberoylanilide hydroxamic acid (SAHA) or erastin on CID.
resultsWe found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells.
conclusionTKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor in the negative effects of TKI by eliminating cisplatin-induced ROS.
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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.