ArticleAnnals of translational medicine2021
Phospho-EGFRTyr992 is synergistically repressed by co-inhibition of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K), which attenuates resistance to erlotinib in head and neck cancer cells.
Article in Annals of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed, 3 citations in OpenAlex.
- 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
- Decoding the research landscape of drug resistance and therapeutic approaches in head and neck cancer: a bibliometric analysis from 2000 to 2023.Frontiers in pharmacology · 2024Article
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7 authors at 2 institutions in 1 country.
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Abstract
backgroundErlotinib is a commonly used epidermal growth factor receptor (EGFR)-targeted therapeutic choice for head and neck squamous cell carcinoma; however, its efficacy is largely compromised by cancer cell resistance. Understanding and targeting the erlotinib adaptive mechanisms of squamous cell carcinoma of the head and neck (HNSCC) cancer cells are still pressing challenges. This study aimed to elucidate the cooperative erlotinib-sensitizing mechanisms of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K) co-inhibition, which will be helpful in gaining a better understanding of the mechanism of EGFR-tyrosine kinase inhibitor (TKI) resistance in head and neck cancer cells.
methodsHigh-content screening (HCS) was performed to analyze the cell counts of different treatment groups and their drug-sensitizing effect phenotype. Western blotting and immunofluorescence staining assays were used to measure and locate the expression of proteins in the FaDu and TU212 cells. Annexin V/PI and DAPI staining were also used to determine the ratio of apoptotic cells and different cell cycle phases.
resultsThe expression of phosphor-EGFRTyr992 was significantly increased in erlotinib-treated FaDu cells compared with dimethyl sulfoxide (DMSO)-treated FaDu cells. Meanwhile, erlotinib + vorinostat + copanlisib jointly attenuated the expression of phosphor-EGFRTyr1068 and phosphor-EGFRTyr992, but stimulated the expression of E-cadherin. Moreover, we found that the tri-drug group also impaired the expression of phosphor-STAT3Ser727 and its relevant activators, including phosphor-SrcTyr416.
conclusionsThese findings indicate that HDACs and PI3K co-inhibition sensitizes erlotinib via inactivation of the phosphor-EGFRTyr1068-induced RTK-STAT3 axis. However, PI3K inhibition was sufficient to sensitize TU212 cells to erlotinib, providing new perspectives for the further clinical study of erlotinib + vorinostat + copanlisib as a potential combination therapeutic solution for EGFR responsive reactivation-induced resistance to erlotinib.
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