ArticleJournal of experimental & clinical cancer research : CR2019
Shisa3 brakes resistance to EGFR-TKIs in lung adenocarcinoma by suppressing cancer stem cell properties.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Overexpression of SLC44A4 suppresses ferroptosis and reduces lipid peroxidationAnnals of medicine · 2026Article
- Activation of the NF-κB/ALDH1A1 signaling promotes non-mutational resistance to EGFR-TKIs in non-small cell lung cancer.Oncogene · 2026Article
- Rare Cancer Explorer 1.0 (RaCE 1.0): a dedicated database and analytical platform focused on rare cancers.Nucleic acids research · 2026Article
- Research progress on the characteristics and functions of m6A modification in lung cancer tumor stem cells.American journal of cancer research · 2026Review
- Sensitive dissection of a genomic regulatory landscape using bulk and targeted single-cell activation.Cell genomics · 2025Article
- Programmed cell death protein 1 in cancer cells.Cell communication and signaling : CCS · 2025Review
- CCDC34 maintains stemness phenotype through β-catenin-mediated autophagy and promotes EGFR-TKI resistance in lung adenocarcinoma.Cancer gene therapy · 2025Article
- Cancer stem cells in personalized therapy: mechanisms, microenvironment crosstalk, and therapeutic vulnerabilities.Frontiers in cell and developmental biology · 2025Review
- Diaryl pyrimidine guanidine suppresses hepatocellular carcinoma cell stemness by targeting β-catenin signaling.Frontiers in oncology · 2025Article
- Role of toll-like receptors in pulmonary immunity: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- Folic Acid-Modified Milk Exosomes Delivering c-Kit siRNA Overcome EGFR-TKIs Resistance in Lung Cancer by Suppressing mTOR Signaling and Stemness.International journal of biological sciences · 2025Article
- SHISA3 Reprograms Tumor-Associated Macrophages Toward an Antitumoral Phenotype and Enhances Cancer Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Identification of cuproptosis-related genes in septic shock based on bioinformatic analysis.PloS one · 2024Article
- Study on Potential Differentially Expressed Genes in Idiopathic Pulmonary Fibrosis by Bioinformatics and Next-Generation Sequencing Data Analysis.Biomedicines · 2023Article
- ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma.Cancer research · 2023Article
- Prostaglandin E2 in neuroblastoma: Targeting synthesis or signaling?Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Review
- Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer.Cell reports · 2022Article
- An extraction from Trametes robiniophila Murr. (Bioengineered · 2022Article
- Claudin1 decrease induced by 1,25-dihydroxy-vitamin D3 potentiates gefitinib resistance therapy through inhibiting AKT activation-mediated cancer stem-like properties in NSCLC cells.Cell death discovery · 2022Article
- Impact of Cancer Stem Cells and Cancer Stem Cell-Driven Drug Resiliency in Lung Tumor: Options in Sight.Cancers · 2022Review
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8 authors.
Funding
Abstract
backgroundAlthough EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. Here, we clarify the function and molecular mechanism of shisa3 as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties.
methodsThe suppresser genes involved in EGFR-TKI resistance were identified and validated by transcriptome sequencing, quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Biological function analyses, cell half maximal inhibitory concentration (IC50), self-renewal, and migration and invasion capacities, were detected by CCK8, sphere formation and Transwell assays. Tumorigenesis and therapeutic effects were investigated in nonobese diabetic/severe combined immunodeficiency (nod-scid) mice. The underlying mechanisms were explored by Western blot and immunoprecipitation analyses.
resultsWe found that low expression of shisa3 was related to EGFR-TKI resistance in lung adenocarcinoma patients. Ectopic overexpression of shisa3 inhibited CSC properties and the cell cycle in the lung adenocarcinoma cells resistant to gefitinib/osimertinib. In contrast, suppression of shisa3 promoted CSC phenotypes and the cell cycle in the cells sensitive to EGFR-TKIs. For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. Furthermore, combinational administration of inhibitors of FGFR/AKT/mTOR and cell cycle signaling could overcome EGFR-TKI resistance associated with shisa3-mediated CSC capacities in vivo.
conclusionTaken together, shisa3 was identified as a brake to EGFR-TKI resistance and CSC characteristics, probably through the FGFR/AKT/mTOR and cell cycle pathways, indicating that shisa3 and concomitant inhibition of its regulated signaling may be a promising therapeutic strategy for reversing EGFR-TKI resistance.
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