Norcantharidin combined with EGFR-TKIs overcomes HGF-induced resistance to EGFR-TKIs in EGFR mutant lung cancer cells via inhibition of Met/PI3k/Akt pathway

Purpose Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exp...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2015-08, Vol.76 (2), p.307-315
Main Authors: Wu, Hongyan, Fan, Fangtian, Liu, Zhaoguo, Shen, Cunsi, Wang, Aiyun, Lu, Yin
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Bridged Bicyclo Compounds, Heterocyclic - therapeutic use
Cancer Research
Cell Line, Tumor
Drug Resistance, Neoplasm - drug effects
Drug Synergism
Hepatocyte Growth Factor - genetics
Hepatocyte Growth Factor - metabolism
Heterografts
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Medicine
Medicine & Public Health
Mice, SCID
Mutation
Neoplasm Transplantation
Oncology
Original Article
Pharmacology/Toxicology
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-met - metabolism
Quinazolines - administration & dosage
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Signal Transduction
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Summary:Purpose Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We examined whether norcantharidin (NCTD), a demethylated analog of cantharidin, could reverse HGF-induced resistance to EGFR-TKIs in mutant lung cancer cells PC-9 and HCC827. Methods MTT assay was used to evaluate cell proliferation of NCTD on PC-9 and HCC827 cells in vitro. Western blotting assays were used to determine the expression of EGFR, p-EGFR (Thr 669), MET, p-MET, AKT, p-AKT (Ser473), PI3kp85, or p-PI3k p85. HGF concentrations were measured by ELISA. HGF-producing cells and PC-9/HGF were established by recombinant adenovirus vectors Ad-GFP-HGF. Xenograft model in SCID mice was used to test the regressive effect of tumor growth on PC-9 cells in vivo. Results NCTD could reverse resistance to EGFR-TKIs induced by exogenous and endogenous HGF in EGFR mutant lung cancer cells via inhibiting the Met/PI3K/Akt pathway. These results suggested that NCTD may be a promising candidate for developing preventive agents against EGFR-TKIs acquired resistance in NSCLC. In the in vivo model, NCTD plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. Conclusions NCTD may be a promising candidate for developing preventive agents against EGFR-TKIs acquired resistance in NSCLC.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-015-2792-x