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Molecular Mechanisms Underlying the Antitumor Activity of 3-Aminopropanamide Irreversible Inhibitors of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer
- Source :
- Neoplasia: An International Journal for Oncology Research, Vol 15, Iss 1, Pp 61-72 (2013), Neoplasia, 15(1), 61-72. Elsevier Inc., Europe PubMed Central, Galvani, E, Giovannetti, E, Saccani, F, Cavazzoni, A, Leon, L G, Dekker, H, Alfieri, R, Carmi, C, Mor, M, Ardizzoni, A, Petronini, P G & Peters, G J 2013, ' Molecular Mechanisms Underlying the Antitumor Activity of 3-Aminopropanamide Irreversible Inhibitors of the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer ', Neoplasia, vol. 15, no. 1, pp. 61-72 . https://doi.org/10.1593/neo.121434
- Publication Year :
- 2013
- Publisher :
- Elsevier, 2013.
-
Abstract
- Overcoming the emergence of acquired resistance to clinically approved epidermal growth factor receptor (EGFR) inhibitors is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). The aimof this study was to investigate the effects of a series of novel compounds affecting viability of NSCLC NCI-H1975 cells (carrying the EGFR T790Mmutation). The inhibition of the autophosphorylation of EGFR occurred at nanomolar concentrations and both UPR1282 and UPR1268 caused a significant induction of apoptosis. Targeting of EGFR and downstream pathways was confirmed by a peptide substrate array, which highlighted the inhibition of other kinases involved in NSCLC cell aggressive behavior. Accordingly, the drugs inhibited migration (about 30%vs. control), which could be, in part, explained also by the increase of E-cadherin expression. Additionally, we observed a contraction of the volume of H1975 spheroids, associated with the reduction of the cancer stem-like cell hallmark CD133. The activity of UPR1282 was retained in H1975 xenograft models where it determined tumor shrinkage (P
- Subjects :
- Cancer Research
Lung Neoplasms
medicine.drug_class
Cell
Mice, Nude
Antineoplastic Agents
Apoptosis
Adenocarcinoma
lcsh:RC254-282
Tyrosine-kinase inhibitor
Mice
Cell Movement
Cancer stem cell
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Epidermal growth factor receptor
Phosphorylation
Lung cancer
Protein Kinase Inhibitors
Cell Proliferation
Mice, Inbred BALB C
biology
Cell growth
Kinase
Gefitinib
Cadherins
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Amides
Xenograft Model Antitumor Assays
ErbB Receptors
medicine.anatomical_structure
Quinazolines
Cancer research
biology.protein
Female
Signal transduction
Signal Transduction
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15228002 and 14765586
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Neoplasia: An International Journal for Oncology Research
- Accession number :
- edsair.doi.dedup.....ae3a42a5c92cfa056120685b640acd22