ArticleEBioMedicine2018
Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization.
Article in EBioMedicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- The components and regulation of the Hippo pathway and its relationships with the progression and treatment of Non-small cell lung cancer (NSCLC).Cancer cell international · 2025Review
- Personalizing Therapy Outcomes through Mitogen-Activated Protein Kinase Pathway Inhibition in Non-Small Cell Lung Cancer.Biomedicines · 2024Review
- Landscape of targeted therapies for lung squamous cell carcinoma.Frontiers in oncology · 2024Review
- OSGIN1 is a novel TUBB3 regulator that promotes tumor progression and gefitinib resistance in non-small cell lung cancer.Cellular and molecular life sciences : CMLS · 2023Article
- Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFRCell death discovery · 2023Article
- Zoledronic acid targets chemo-resistant polyploid giant cancer cells.Scientific reports · 2023Article
- Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1.Cell death discovery · 2022Article
- Atypical activation of signaling downstream of inactivated Bcr-Abl mediates chemoresistance in chronic myeloid leukemia.Journal of cell communication and signaling · 2022Article
- Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma.International journal of molecular sciences · 2022Review
- Review
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- Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer.Cell death discovery · 2021Article
- Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2021Article
- Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer.Cell death & disease · 2021Article
- Hippo signaling: bridging the gap between cancer and neurodegenerative disorders.Neural regeneration research · 2021Article
- ORP8 induces apoptosis by releasing cytochrome c from mitochondria in non‑small cell lung cancer.Oncology reports · 2020Article
- Article
- Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity.International journal of molecular sciences · 2020Review
- Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy.The Journal of pharmacology and experimental therapeutics · 2019Article
- Involvement of SNX1 in regulating EGFR endocytosis in a gefitinib-resistant NSCLC cell lines.Cancer drug resistance (Alhambra, Calif.) · 2019Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC.
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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.