ArticleWorld journal of gastroenterology2012
Insights into erlotinib action in pancreatic cancer cells using a combined experimental and mathematical approach.
Article in World journal of gastroenterology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Article
- Mathematical Modeling to Address Challenges in Pancreatic Cancer.Current topics in medicinal chemistry · 2020Article
- Intramyocardial angiogenetic stem cells and epicardial erythropoietin save the acute ischemic heart.Disease models & mechanisms · 2018Article
- SAHA, an HDAC inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Identifying Determinants of EGFR-Targeted Therapeutic Biochemical Efficacy Using Computational Modeling.CPT: pharmacometrics & systems pharmacology · 2014Article
- Biological and molecular effects of small molecule kinase inhibitors on low-passage human colorectal cancer cell lines.BioMed research international · 2014Article
- Genetic and molecular alterations in pancreatic cancer: implications for personalized medicine.Medical science monitor : international medical journal of experimental and clinical research · 2013Review
- Capturing drug responses by quantitative promoter activity profiling.CPT: pharmacometrics & systems pharmacology · 2013Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimTo gain insights into the molecular action of erlotinib in pancreatic cancer (PC) cells.
methodsTwo PC cell lines, BxPC-3 and Capan-1, were treated with various concentrations of erlotinib, the specific mitogen-activated protein kinase kinase (MEK) inhibitor U0126, and protein kinase B (AKT) inhibitor XIV. DNA synthesis was measured by 5-bromo-2'-deoxyuridine (BrdU) assays. Expression and phosphorylation of the epidermal growth factor receptor (EGFR) and downstream signaling molecules were quantified by Western blot analysis. The data were processed to calibrate a mathematical model, based on ordinary differential equations, describing the EGFR-mediated signal transduction.
resultsErlotinib significantly inhibited BrdU incorporation in BxPC-3 cells at a concentration of 1 μmol/L, whereas Capan-1 cells were much more resistant. In both cell lines, MEK inhibitor U0126 and erlotinib attenuated DNA synthesis in a cumulative manner, whereas the AKT pathway-specific inhibitor did not enhance the effects of erlotinib. While basal phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) did not differ much between the two cell lines, BxPC-3 cells displayed a more than five-times higher basal phospho-AKT level than Capan-1 cells. Epidermal growth factor (EGF) at 10 ng/mL induced the phosphorylation of EGFR, AKT and ERK in both cell lines with similar kinetics. In BxPC-3 cells, higher levels of phospho-AKT and phospho-ERK (normalized to the total protein levels) were observed. Independent of the cell line, erlotinib efficiently inhibited phosphorylation of EGFR, AKT and ERK. The mathematical model successfully simulated the experimental findings and provided predictions regarding phosphoprotein levels that could be verified experimentally.
conclusionOur data suggest basal AKT phosphorylation and the degree of EGF-induced activation of AKT and ERK as molecular determinants of erlotinib efficiency in PC cells.
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